alpha-synuclein and Tauopathies

alpha-synuclein has been researched along with Tauopathies* in 74 studies

Reviews

17 review(s) available for alpha-synuclein and Tauopathies

ArticleYear
Targeting alpha-synuclein or tau for treating neurodegenerative movement disorders.
    Revue neurologique, 2022, Volume: 178, Issue:5

    The two commonest groups of neurodegenerative disorders causing movement disorders are synucleinopathies and tauopathies. These disorders are characterised by the accumulation of abnormally misfolded forms of α-synuclein and tau proteins. Our current understanding of their pathogenesis suggests that extracellular forms of these proteins are of major relevance to the mechanism of pathology propagation throughout the brain and disease progression. The most novel approaches to find disease-modifying therapies aim to reduce or block these forms of tau and α-synuclein. This article reviews therapeutic strategies targeting α-synuclein and tau protein which have entered clinical development.

    Topics: alpha-Synuclein; Humans; Movement Disorders; Neurodegenerative Diseases; tau Proteins; Tauopathies

2022
Structures of tau and α-synuclein filaments from brains of patients with neurodegenerative diseases.
    Neurochemistry international, 2022, Volume: 158

    Intracellular accumulations and aggregates of abnormal protein, consisting of amyloid-like fibrils, are common neuropathological features of many neurodegenerative diseases. The distributions and spreading of these pathological proteins are closely correlated with clinical symptoms and progression. Recent evidence supports the idea that template-mediated amplification of amyloid-like fibrils and intracellular propagation of fibril seeds are the main mechanisms by which pathological features spread along the neural circuits in the brain. Here, we review recent developments in the structural analysis of amyloid-like fibrils from brains of patients with various types of tauopathy and α-synucleinopathy, focusing on cryo-electron microscopy and mass analysis, and we discuss their relevance to the mechanisms of template-mediated amplification and intracellular propagation.

    Topics: alpha-Synuclein; Amyloid; Brain; Cryoelectron Microscopy; Humans; Neurodegenerative Diseases; tau Proteins; Tauopathies

2022
The emerging role of LRRK2 in tauopathies.
    Clinical science (London, England : 1979), 2022, 07-15, Volume: 136, Issue:13

    Parkinson's disease (PD) is conventionally described as an α-synuclein aggregation disorder, defined by Lewy bodies and neurites, and mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common autosomal dominant cause of PD. However, LRRK2 mutations may be associated with diverse pathologies in patients with Parkinson's syndrome including tau pathology resembling progressive supranuclear palsy (PSP). The recent discovery that variation at the LRRK2 locus is associated with the progression of PSP highlights the potential importance of LRRK2 in tauopathies. Here, we review the emerging evidence and discuss the potential impact of LRRK2 dysfunction on tau aggregation, lysosomal function, and endocytosis and exocytosis.

    Topics: alpha-Synuclein; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Tauopathies

2022
From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases.
    International journal of molecular sciences, 2021, Jan-18, Volume: 22, Issue:2

    A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region- and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin.

    Topics: alpha-Synuclein; Humans; Neurodegenerative Diseases; Phenotype; Prion Proteins; Protein Conformation; Protein Processing, Post-Translational; Substrate Specificity; Synucleinopathies; tau Proteins; Tauopathies

2021
Cell-to-Cell Transmission of Tau and α-Synuclein.
    Trends in molecular medicine, 2020, Volume: 26, Issue:10

    The stereotypical spread of pathological protein inclusions and clinicopathological heterogeneity are well described in neurodegenerative diseases. Accumulating evidence suggests that the former can be attributed to consecutive cell-to-cell transmission of pathological proteins between anatomically connected brain regions, while the latter has been hypothesized to result from the spread of conformationally distinct pathological protein aggregates, or strains. These emerging concepts have dramatically changed our understanding of neurodegenerative diseases. In this review, we first summarize the background and recent findings underpinning these concepts with a focus on two major pathological proteins: tau and α-synuclein. We then discuss their clinical implications for tauopathies and synucleinopathies and propose a working hypothesis for future research.

    Topics: alpha-Synuclein; Animals; Humans; Neurodegenerative Diseases; tau Proteins; Tauopathies

2020
Vaccination strategies in tauopathies and synucleinopathies.
    Journal of neurochemistry, 2017, Volume: 143, Issue:5

    Vaccination therapies constitute potential treatment options in neurodegenerative disorders such as Alzheimer disease or Parkinson disease. While a lot of research has been performed on vaccination against extracellular amyloid β, the focus recently shifted toward vaccination against the intracellular proteins tau and α-synuclein, with promising results in terms of protein accumulation reduction. In this review, we briefly summarize lessons to be learned from clinical vaccination trials in Alzheimer disease that target amyloid β. We then focus on tau and α-synuclein. For both proteins, we provide important data on protein immunogenicity, and put them into context with data available from both animals and human vaccination trials targeted at tau and α-synuclein. Together, we give a comprehensive overview about current clinical data, and discuss associated problems.

    Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Parkinson Disease; Tauopathies; Vaccination

2017
Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: Examples of amyloidopathies, tauopathies and synucleinopathies.
    Progress in neurobiology, 2017, Volume: 155

    Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative diseases that generate important health-related direct and indirect socio-economic costs. They are characterized by severe neuronal losses in several disease-specific brain regions associated with deposits of aggregated proteins. In Alzheimer's disease, β-amyloid peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein tau are the two main neuropathological lesions, while Parkinson's disease is defined by the presence of Lewy Bodies that are intraneuronal proteinaceous cytoplasmic inclusions. α-Synuclein has been identified as a major protein component of Lewy Bodies and heavily implicated in the pathogenesis of Parkinson's disease. In the past few years, evidence has emerged to explain how these aggregate-prone proteins can undergo spontaneous self-aggregation, propagate from cell to cell, and mediate neurotoxicity. Current research now indicates that oligomeric forms are probably the toxic species. This article discusses recent progress in the understanding of the pathogenesis of these diseases, with a focus on the underlying mechanisms of protein aggregation, and emphasizes the pathophysiological molecular mechanisms leading to cellular toxicity. Finally, we present the putative direct link between β-amyloid peptide and tau in causing toxicity in Alzheimer's disease as well as α-synuclein in Parkinson's disease, along with some of the most promising therapeutic strategies currently in development for those incurable neurodegenerative disorders.

    Topics: alpha-Synuclein; Alzheimer Disease; Animals; Humans; Nerve Degeneration; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregation, Pathological; Tauopathies

2017
Prion-like properties of Tau protein: the importance of extracellular Tau as a therapeutic target.
    The Journal of biological chemistry, 2014, Jul-18, Volume: 289, Issue:29

    Work over the past 4 years indicates that multiple proteins associated with neurodegenerative diseases, especially Tau and α-synuclein, can propagate aggregates between cells in a prion-like manner. This means that once an aggregate is formed it can escape the cell of origin, contact a connected cell, enter the cell, and induce further aggregation via templated conformational change. The prion model predicts a key role for extracellular protein aggregates in mediating progression of disease. This suggests new therapeutic approaches based on blocking neuronal uptake of protein aggregates and promoting their clearance. This will likely include therapeutic antibodies or small molecules, both of which can be developed and optimized in vitro prior to preclinical studies.

    Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Membrane; Heparan Sulfate Proteoglycans; Humans; Prions; Protein Conformation; Protein Multimerization; Protein Transport; tau Proteins; Tauopathies; Vaccines

2014
Prions: generation and spread versus neurotoxicity.
    The Journal of biological chemistry, 2014, Jul-18, Volume: 289, Issue:29

    Neurodegenerative diseases are characterized by the aggregation of misfolded proteins in the brain. Among these disorders are the prion diseases, which are transmissible, and in which the misfolded proteins ("prions") are also the infectious agent. Increasingly, it appears that misfolded proteins in Alzheimer and Parkinson diseases and the tauopathies also propagate in a "prion-like" manner. However, the association between prion formation, spread, and neurotoxicity is not clear. Recently, we showed that in prion disease, protein misfolding leads to neurodegeneration through dysregulation of generic proteostatic mechanisms, specifically, the unfolded protein response. Genetic and pharmacological manipulation of the unfolded protein response was neuroprotective despite continuing prion replication, hence dissociating this from neurotoxicity. The data have clear implications for treatment across the spectrum of these disorders, targeting pathogenic processes downstream of protein misfolding.

    Topics: Adenine; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; eIF-2 Kinase; Humans; Indoles; Neurodegenerative Diseases; Parkinson Disease; Prion Diseases; Prions; Protein Conformation; Protein Kinase Inhibitors; tau Proteins; Tauopathies; Unfolded Protein Response

2014
[The role of proteins in neurodegenerative disease].
    Postepy higieny i medycyny doswiadczalnej (Online), 2012, Apr-16, Volume: 66

     All neurodegenerative diseases are related to pathology and accumulation of proteins. Proteins are basic structural and functional components of each cell and their functions are associated with their amino acid composition and spatial structure. The proper functioning of protein is necessary for the proper operation of the body system. In the case of disorders of proteins' spatial structure, the development of pathological processes may occur. Accumulation of abnormal proteins is toxic to nerve cells and causes neurodegeneration. Different disorders are characterized by abnormalities of various proteins. This type of neurodegenerative diseases includes Parkinson's disease, tauopathies, Alzheimer's disease, and prion diseases. Parkinson's disease is characterized by toxicity of α-synuclein. The pathology of tau protein is specific for tauopathies, prion protein for prion diseases. In the case of Alzheimer's disease it is β-amyloid. All proteins responsible for the pathology are present in the physiological state in the organism. Damage to the area of the brain covered by the pathological process and the clinical symptoms are characteristic for a particular type of disease. Detailed knowledge of the mechanisms of the disease can be an important element in the development of effective ways of treatment.

    Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Humans; Molecular Structure; Neurodegenerative Diseases; Neurons; Parkinson Disease; Prion Diseases; Prions; Synaptic Transmission; tau Proteins; Tauopathies

2012
Neuropathology of non-Alzheimer degenerative disorders.
    International journal of clinical and experimental pathology, 2009, Aug-25, Volume: 3, Issue:1

    Neurodegenerative diseases are characterized by selective and progressive loss of specific populations of neurons, which determines the clinical presentation. The same neuronal populations can be affected in a number of different disorders. Given that the clinical presentation reflects the particular population of neurons that are targets of the disease process, it is clear that for any given clinical syndrome, more than one neurodegenerative disease can account for the clinical syndrome. Because of this clinical ambiguity, for the purpose of this brief review neurodegenerative disorders are classified according to the underlying molecular pathology rather than their clinical presentation. The major neurodegenerative diseases can be classified into amyloidoses, tauopathies, alpha-synucleinopathies and TDP-43 proteinopathies.

    Topics: alpha-Synuclein; Amyloidosis; Gene Expression; Humans; Neurodegenerative Diseases; Neurons; Pathology, Molecular; Syndrome; Tauopathies; TDP-43 Proteinopathies

2009
[Nosology of dementias: the neuropathologist's point of view].
    Revue neurologique, 2006, Volume: 162, Issue:10

    The diagnosis of degenerative dementias heavily relies on the identification of neuronal or glial inclusions. Tauopathy is probably the largest group including Alzheimer and Pick disease, mutation of the tau gene, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. Lewy bodies, when numerous in the cerebral cortex, are usually associated with the cognitive deficit of Parkinson disease dementia or of dementia with Lewy bodies--both conditions being distinguished by clinical information. The inclusions of the dentate gyrus, only labeled by anti-ubiquitin antibodies, isolate a subgroup of fronto-temporal dementia (FTDu), sometimes familial and sometimes associated with amyotrophic lateral sclerosis. Mutations of the progranulin gene have been recently discovered among a significant proportion of these patients. Neuronal Intermediate Filament Inclusion Disease (NIFID) is a rare, apparently sporadic dementia, characterized by the presence of large inclusions in the cell body of many neurons. These inclusions react with antibodies directed against neurofilaments or against other intermediate filaments (such as alpha-internexin). The diagnostic value of some of these inclusions allowing the classification of the degenerative dementias has been discussed. The link between the inclusions and the pathogenetic mechanism is indeed probably variable. It should however be stressed that whenever their composition has been elucidated, the inclusions have given important clues to the pathogenesis of the disease in which they had been found.

    Topics: Aged; alpha-Synuclein; Alzheimer Disease; Brain; Dementia; Humans; Neurodegenerative Diseases; Oligodendroglia; Pick Disease of the Brain; Tauopathies; Ubiquitin

2006
Animal models of tauopathies.
    Neuropathology : official journal of the Japanese Society of Neuropathology, 2006, Volume: 26, Issue:5

    Intracellular fibrillar amyloid lesions comprised of tau proteins are pathological hallmarks in diverse neurodegenerative disorders. As models of these tauopathies, transgenic mice overexpressing tau with or without mutations discovered in familial tauopathies were generated. Findings in these tau transgenic mice support the notion that impairments of tau proteins are causally related to tauopathies, while studies on crossbred mice have indicated initiation and promotion of tau-positive neuropathologies by crosstalk among several pathogenic molecules. Enhancement of tau pathology by amyloid beta (Abeta) deposition provided some of the most compelling evidence for such a cross-talk, and molecular processes linking abnormalities of Abeta and tan have been suggested to involve activation of calcium-dependent protease, calpain, based on analyses of amyloid precursor protein transgenic mice crossbred with other genetically engineered mice with altered calpain activity. It also should be noted that mice transgenic for both tau and alpha-synuclein exhibit facilitated polymerization of these molecules into pathological filaments. Roles of fibrillar tau deposits in nervous system injuries can be mechanistically pursued by longitudinal monitoring of brain amyloidosis and neuroglial degeneration in the time course of antiamyloid intervention. The possibility of in vivo detection of tau-positive amyloid lesions has been demonstrated by intravenous administration of potential tracers into tau transgenic mice and subsequent brain imaging. Moreover, visualization of glial responses in living brains may allow sensitive detection of degenerative changes in the central nervous system.

    Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Mice; Mice, Transgenic; tau Proteins; Tauopathies

2006
Role of DJ-1 in Parkinson's disease.
    Journal of molecular neuroscience : MN, 2006, Volume: 29, Issue:3

    Parkinson's disease (PD), one of the most common neurodegenerative diseases, is a multifactorial disease caused by both genetic and environmental factors. Although most patients suffering from PD have a sporadic disease, several genetic causes have been identified in recent years, including alpha-synuclein, parkin, PINK1, dardarin (LRRK2), and DJ-1. DJ-1 deletions and point mutations have been found worldwide, and loss of functional protein was shown to cause autosomal recessive PD. Moreover, DJ-1 immunoreactive inclusions are found in other alpha-synucleopathies and tauopathies, indicating that different neurodegenerative diseases might share a common mechanism in which DJ-1 might play a key role. The function of DJ-1 is still unknown; however, it is associated with various cellular processes, including response to oxidative stress, cellular transformation, RNAbinding, androgen-receptor signaling, spermatogenesis, and fertilization. This article reviews the current knowledge on DJ-1, focusing on its importance in the pathogenesis of PD.

    Topics: alpha-Synuclein; Animals; Cell Transformation, Viral; Dopamine; Drosophila melanogaster; Drosophila Proteins; Genes, Recessive; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Mutation; Nerve Degeneration; Nerve Tissue Proteins; Oncogene Proteins; Oxidative Stress; Parkinsonian Disorders; Peroxiredoxins; Protein Deglycase DJ-1; Tauopathies; Ubiquitin-Protein Ligases

2006
alpha-Synuclein: a potent inducer of tau pathology.
    Experimental neurology, 2005, Volume: 192, Issue:2

    Topics: alpha-Synuclein; Animals; Humans; Nerve Tissue Proteins; Neurofibrillary Tangles; Synucleins; tau Proteins; Tauopathies

2005
Following the leader: fibrillization of alpha-synuclein and tau.
    Experimental neurology, 2004, Volume: 187, Issue:2

    Topics: alpha-Synuclein; Animals; Humans; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurofibrillary Tangles; Phosphorylation; Protein Structure, Tertiary; Synucleins; tau Proteins; Tauopathies

2004
[Neuropathology of tauopathies and synucleinopathies, and neuroanatomy of sleep disorders: meeting the challenge].
    Revue neurologique, 2003, Volume: 159, Issue:11 Suppl

    Abnormalities of tau and alpha-synuclein have been described in a variety of neurodegenerative diseases often associated with sleep disorders. Neuropathological descriptions concerning these diseases are rapidly expanding, and they become difficult to summarise. On the other hand, the human neuroanatomy of sleep remains an ill defined issue. Main tauopathies are Alzheimer's disease, progressive supranuclear palsy, cortico-basal degeneration, argyrophilic grain disease, Pick disease and fronto-temporal degeneration with Parkinsonism associated with chromosome 17. In contrast to Alzheimer's disease, where abnormal tau containing cells are mainly neurones, in the other disorders, both neurones and glial cells are affected. The presynaptic protein alpha-synuclein is a major constituent of Lewy-type lesions in Parkinson disease and in dementia with Lewy bodies. Alpha-synuclein is also found in neurones and glia of Multi System Atrophy. This led to group these disorders into the still ill defined group of synucleinopathies. The lesions of tauopathies and synucleinopathies are presented, and their distribution in the most common disorders is described, distinguishing when possible neuronal loss and neuropathological markers. Recent data show that their extension is far larger than previously assumed and that they involve a variety of areas possibly involved in sleep regulation. Sleep disorders have been described in various tauopathies and synucleinopathies. However, no detailed clinico-pathological reports concerning the distribution of affected and spared areas in patients studied by polysomnography are available. Furthermore, the similarities of sleep disorders associated with different diseases, the interindividual variability, the frequently associated disorders, and the difficulties in quantifying neuronal loss make any clinicopathological correlation uncertain. The knowledge of sleep neuroanatomy is mainly based on animal studies. The few data concerning the structures of human brain areas involved in sleep organisation are recalled. Several systems known to be acting in sleep physiology are usually affected by tauopathies and synucleinopathies, but the pattern of their involvement in sleep pathology remains highly conjectural. The neuropathology of sleep disorders in tauopathies and synucleinopathies is a still uncultivated field.

    Topics: Adult; Aged; alpha-Synuclein; Brain Chemistry; Humans; Lewy Bodies; Middle Aged; Nerve Tissue Proteins; Neurodegenerative Diseases; Sleep Wake Disorders; Synucleins; tau Proteins; Tauopathies

2003

Other Studies

57 other study(ies) available for alpha-synuclein and Tauopathies

ArticleYear
Ashwagandha- Withania somnifera (L.) Dunal as a multipotent neuroprotective remedy for genetically induced motor dysfunction and cellular toxicity in human neurodegenerative disease models of Drosophila.
    Journal of ethnopharmacology, 2024, Jan-10, Volume: 318, Issue:Pt A

    Ashwagandha-Withania somnifera (L.) Dunal, well known for its multipotent therapeutic properties has been used in Ayurveda for 3000 years. The plant with more than 50 active phytoconstituents is recognised for its anti-cancerous, anti-diabetic, anti-inflammatory, anti-microbial, and neurotherapeutic properties demonstrated in in vitro studies and chemically induced rodent models. Genetically targeted Parkinson's, Alzheimer's and other neurodegenerative disease models have been created in Drosophila and have been used to get mechanistic insight into the in vivo cellular events, and genetic pathways that underlie respective neurodegenerative condition. But hitherto, there aren't enough attempts made to capitalize the genetic potential of these disease models to validate the therapeutic efficacy of different reagents used in traditional medicine, in the context of specific disease-causing genetic mutations.. Drugs discovered using in vitro platforms might fail in several instances of clinical trials because of the genetic heterogeneity and variability in the physiological context found among the patients. Drosophila by virtue of its genetically regulated experimental potential forms an ideal in vivo model to validate the candidate reagents discovered in in vitro screens for their efficacy under specific genetic situations. Here we have used genetically induced α-synucleinopathy and tauopathy transgenic fly models to study the efficacy of Ashwagandha treatment, assessing cellular and behavioural parameters.. We have expressed the disease-causing human gene mutations in specific cell types of Drosophila using GAL4/UAS targeted expression system to create disease models. Human α-synuclein mutant (A30P) was expressed in dopaminergic neurons using Ddc-GAL4 driver strain to induce dopaminergic neurodegeneration and assayed for motor dysfunction. Human Tau. Lifespan assay shows that, Ashwagandha-root extract imparts an extended lifespan in male Drosophila flies which are intrinsically less stress resistant. Motor dysfunction caused due to human α-synuclein mutant protein expressed in dopaminergic neurons is greatly brought down. Further, Ashwagandha extract treatment significantly reduces Tau. We have carried out a multifaceted study which elucidates that Ashwagandha can serve as a comprehensive, phytotherapeutic formulation to combat neurodegeneration, targeting multiple causative genetically defective conditions.

    Topics: alpha-Synuclein; Animals; Drosophila; Humans; Neurodegenerative Diseases; Plant Extracts; Tauopathies; Withania

2024
Tau seeds occur before earliest Alzheimer's changes and are prevalent across neurodegenerative diseases.
    Acta neuropathologica, 2023, Volume: 146, Issue:1

    Tau neurofibrillary tangles are a hallmark of Alzheimer's disease neuropathological change. However, it remains largely unclear how distinctive Alzheimer's disease tau seeds (i.e. 3R/4R) correlate with histological indicators of tau accumulation. Furthermore, AD tau co-pathology is thought to influence features and progression of other neurodegenerative diseases including Lewy body disease; yet measurements of different types of tau seeds in the setting of such diseases is an unmet need. Here, we use tau real-time quaking-induced conversion (RT-QuIC) assays to selectively quantitate 3R/4R tau seeds in the frontal lobe which accumulates histologically identifiable tau pathology at late disease stages of AD neuropathologic change. Seed quantitation across a spectrum of neurodegenerative disease cases and controls indicated tau seeding activity can be detected well before accompanying histopathological indication of tau deposits, and even prior to the earliest evidence of Alzheimer's-related tau accumulation anywhere in the brain. In later stages of AD, 3R/4R tau RT-QuIC measures correlated with immunohistochemical tau burden. In addition, Alzheimer's tau seeds occur in the vast majority of cases evaluated here inclusive of primary synucleinopathies, frontotemporal lobar degeneration and even controls albeit at multi-log lower levels than Alzheimer's cases. α-synuclein seeding activity confirmed synucleinopathy cases and further indicated the co-occurrence of α-synuclein seeds in some Alzheimer's disease and primary tauopathy cases. Our analysis indicates that 3R/4R tau seeds in the mid-frontal lobe correlate with the overall Braak stage and Alzheimer's disease neuropathologic change, supporting the quantitative predictive value of tau RT-QuIC assays. Our data also indicate 3R/4R tau seeds are elevated in females compared to males at high (≥ IV) Braak stages. This study suggests 3R/4R tau seeds are widespread even prior to the earliest stages of Alzheimer's disease changes, including in normal, and even young individuals, with prevalence across multiple neurodegenerative diseases to further define disease subtypes.

    Topics: alpha-Synuclein; Alzheimer Disease; Female; Humans; Male; Neurodegenerative Diseases; Synucleinopathies; tau Proteins; Tauopathies

2023
Single-domain antibody-based noninvasive in vivo imaging of α-synuclein or tau pathology.
    Science advances, 2023, 05-10, Volume: 9, Issue:19

    Intracellular deposition of α-synuclein and tau are hallmarks of synucleinopathies and tauopathies, respectively. Recently, several dye-based imaging probes with selectivity for tau aggregates have been developed, but suitable imaging biomarkers for synucleinopathies are still unavailable. Detection of both of these aggregates early in the disease process may allow for prophylactic therapies before functional impairments have manifested, highlighting the importance of developing specific imaging probes for these lesions. In contrast to the β sheet dyes, single-domain antibodies, found in camelids and a few other species, are highly specific, and their small size allows better brain entry and distribution than whole antibodies. Here, we have developed such imaging ligands via phage display libraries derived from llamas immunized with α-synuclein and tau preparations, respectively. These probes allow noninvasive and specific in vivo imaging of α-synuclein versus tau pathology in mice, with the brain signal correlating strongly with lesion burden. These small antibody derivatives have great potential for in vivo diagnosis of these diseases.

    Topics: alpha-Synuclein; Animals; Antibodies; Coloring Agents; Mice; Single-Domain Antibodies; Synucleinopathies; tau Proteins; Tauopathies

2023
An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology.
    Neuron, 2023, 08-02, Volume: 111, Issue:15

    The circadian clock protein BMAL1 modulates glial activation and amyloid-beta deposition in mice. However, the effects of BMAL1 on other aspects of neurodegenerative pathology are unknown. Here, we show that global post-natal deletion of Bmal1 in mouse tauopathy or alpha-synucleinopathy models unexpectedly suppresses both tau and alpha-synuclein (αSyn) aggregation and related pathology. Astrocyte-specific Bmal1 deletion is sufficient to prevent both αSyn and tau pathology in vivo and induces astrocyte activation and the expression of Bag3, a chaperone critical for macroautophagy. Astrocyte Bmal1 deletion enhances phagocytosis of αSyn and tau in a Bag3-dependent manner, and astrocyte Bag3 overexpression is sufficient to mitigate αSyn spreading in vivo. In humans, BAG3 is increased in patients with AD and is highly expressed in disease-associated astrocytes (DAAs). Our results suggest that early activation of astrocytes via Bmal1 deletion induces Bag3 to protect against tau and αSyn pathologies, providing new insights into astrocyte-specific therapies for neurodegeneration.

    Topics: Adaptor Proteins, Signal Transducing; alpha-Synuclein; Amyloid beta-Peptides; Animals; Apoptosis Regulatory Proteins; ARNTL Transcription Factors; Astrocytes; Humans; Mice; Synucleinopathies; tau Proteins; Tauopathies

2023
O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies.
    ACS chemical neuroscience, 2022, 04-20, Volume: 13, Issue:8

    Neurodegenerative proteinopathies are characterized by the intracellular formation of insoluble and toxic protein aggregates in the brain that are closely linked to disease progression. In Alzheimer's disease and in rare tauopathies, aggregation of the microtubule-associated tau protein leads to the formation of neurofibrillary tangles (NFT). In Parkinson's disease (PD) and other α-synucleinopathies, intracellular Lewy bodies containing aggregates of α-synuclein constitute the pathological hallmark. Inhibition of the glycoside hydrolase O-GlcNAcase (OGA) prevents the removal of O-linked

    Topics: alpha-Synuclein; Animals; beta-N-Acetylhexosaminidases; Mice; Parkinson Disease; Pharmaceutical Preparations; Synucleinopathies; tau Proteins; Tauopathies

2022
Combined CSF α-SYN RT-QuIC, CSF NFL and midbrain-pons planimetry in degenerative parkinsonisms: From bedside to bench, and back again.
    Parkinsonism & related disorders, 2022, Volume: 99

    Differential diagnosis between Parkinson's disease (PD) and atypical parkinsonisms (APs: multiple system atrophy[MSA], progressive supranuclear palsy[PSP], corticobasal degeneration[CBD]) remains challenging. Lately, cerebrospinal fluid (CSF) studies of neurofilament light-chain (NFL) and RT-QuIC of alpha-synuclein (α-SYN) have shown promise, but data on their combination with MRI measures is lacking.. (1) to assess the combined diagnostic ability of CSF RT-QuIC α-SYN, CSF NFL and midbrain/pons MRI planimetry in degenerative parkinsonisms; (2) to evaluate if biomarker-signatures relate to clinical diagnoses and whether or not unexpected findings can guide diagnostic revision.. We collected demographic and clinical data and set up α-SYN RT-QuIC at our lab in a cross-sectional cohort of 112 participants: 19 control subjects (CSs), 20PD, 37MSA, 23PSP, and 13CBD cases. We also determined CSF NFL by ELISA and, in 74 participants (10CSs, 9PD, 26MSA, 19PSP, 10CBD), automatized planimetric midbrain/pons areas from 3T-MRI.. Sensitivity of α-SYN RT-QuIC for PD was 75% increasing to 81% after revisiting clinical diagnoses with aid of biomarkers. Sensitivity for MSA was 12% but decreased to 9% with diagnostic revision. Specificities were 100% against CSs, and 89% against tauopathies raising to 91% with diagnostic revision. CSF NFL was significantly higher in APs. The combination of biomarkers yielded high diagnostic accuracy (PD vs. non-PD AUC = 0.983; MSA vs. non-MSA AUC = 0.933; tauopathies vs. non-tauopathies AUC = 0.924). Biomarkers-signatures fitted in most cases with clinical classification.. The combination of CSF NFL, CSF RT-QuIC α-SYN and midbrain/pons MRI measures showed high discriminant ability across all groups. Results opposite to expected can assist diagnostic reclassification.

    Topics: alpha-Synuclein; Biomarkers; Cross-Sectional Studies; Humans; Mesencephalon; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Pons; Tauopathies

2022
Parkinson's Disease Etiology: Insights and Associations with Phosphate Toxicity.
    International journal of molecular sciences, 2022, Jul-22, Volume: 23, Issue:15

    The present paper investigated the association of Parkinson's disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson's disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson's disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson's disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson's disease. Sarcopenia and cancer in Parkinson's disease patients are also associated with phosphate toxicity. Additionally, Parkinson's disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson's disease.

    Topics: alpha-Synuclein; Humans; Lewy Body Disease; Mitochondrial Permeability Transition Pore; Parkinson Disease; Phosphates; Tauopathies

2022
Granulovacuolar degeneration bodies are independently induced by tau and α-synuclein pathology.
    Alzheimer's research & therapy, 2022, 12-14, Volume: 14, Issue:1

    Granulovacuolar degeneration bodies (GVBs) are intracellular vesicular structures that commonly accompany pathological tau accumulations in neurons of patients with tauopathies. Recently, we developed the first model for GVBs in primary neurons, that requires exogenous tau seeds to elicit tau aggregation. This model allowed the identification of GVBs as proteolytically active lysosomes induced by tau pathology. GVBs selectively accumulate cargo in a dense core, that shows differential and inconsistent immunopositivity for (phosphorylated) tau epitopes. Despite the strong evidence connecting GVBs to tau pathology, these structures have been reported in neurons without apparent pathology in brain tissue of tauopathy patients. Additionally, GVBs and putative GVBs have also been reported in the brain of patients with non-tau proteinopathies. Here, we investigated the connection between pathological protein assemblies and GVBs in more detail.. This study combined newly developed primary neuron models for tau and α-synuclein pathology with observations in human brain tissue from tauopathy and Parkinson's disease patients. Immunolabeling and imaging techniques were employed for extensive characterisation of pathological proteins and GVBs. Quantitative data were obtained by high-content automated microscopy as well as single-cell analysis of confocal images.. Employing a novel seed-independent neuronal tau/GVB model, we show that in the context of tauopathy, GVBs are inseparably associated with the presence of cytosolic pathological tau and that intracellular tau aggregation precedes GVB formation, strengthening the causal relationship between pathological accumulation of tau and GVBs. We also report that GVBs are inseparably associated with pathological tau at the single-cell level in the hippocampus of tauopathy patients. Paradoxically, we demonstrate the presence of GVBs in the substantia nigra of Parkinson's disease patients and in a primary neuron model for α-synuclein pathology. GVBs in this newly developed α-synuclein/GVB model are induced in the absence of cytosolic pathological tau accumulations. GVBs in the context of tau or α-synuclein pathology showed similar immunoreactivity for different phosphorylated tau epitopes. The phosphorylated tau immunoreactivity signature of GVBs is therefore independent of the presence of cytosolic tau pathology.. Our data identify the emergence of GVBs as a more generalised response to cytosolic protein pathology.

    Topics: alpha-Synuclein; Epitopes; Humans; Nerve Degeneration; Parkinson Disease; tau Proteins; Tauopathies

2022
α-synuclein abnormalities trigger focal tau pathology, spreading to various brain areas in Parkinson disease.
    Journal of neurochemistry, 2021, Volume: 157, Issue:3

    Parkinson disease (PD) is the second most common neurodegenerative disorder, whose prevalence is 2~3% in the population over 65. α-Synuclein aggregation is the major pathological hallmark of PD. However, recent studies have demonstrated enhancing evidence of tau pathology in PD. Despite extensive considerations, thus far, the actual spreading mechanism of neurodegeneration has remained elusive in a PD brain. This study aimed to further investigate the development of α-synuclein and tau pathology. We employed various PD models, including cultured neurons treated with either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or with recombinant α-synuclein. Also, we studied dopaminergic neurons of cytokine Interferon-β knock-out. Moreover, we examined rats treated with 6-hydroxydopamine, Rhesus monkeys administrated with MPTP neurotoxin, and finally, human post-mortem brains. We found the α-synuclein phosphorylation triggers tau pathogenicity. Also, we observed more widespread phosphorylated tau than α-synuclein with prion-like nature in various brain areas. We optionally removed P-tau or P-α-synuclein from cytokine interferon-β knock out with respective monoclonal antibodies. We found that tau immunotherapy suppressed neurodegeneration more than α-synuclein elimination. Our findings indicate that the pathogenic tau could be one of the leading causes of comprehensive neurodegeneration triggered by PD. Thus, we can propose an efficient therapeutic target to fight the devastating disorder.

    Topics: alpha-Synuclein; Animals; Autopsy; Behavior, Animal; Brain; Cell Survival; Dopaminergic Neurons; Female; Humans; Interferon-beta; Macaca mulatta; Male; Mice; Mice, Knockout; MPTP Poisoning; Parkinson Disease; Pregnancy; Rats; Rats, Wistar; Recombinant Proteins; tau Proteins; Tauopathies

2021
Bispecific Tau Antibodies with Additional Binding to C1q or Alpha-Synuclein.
    Journal of Alzheimer's disease : JAD, 2021, Volume: 80, Issue:2

    Alzheimer's disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson's disease and Lewy body dementia also frequently occur together with tau pathology.. Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway.. Herein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q.. Affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway.. Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

    Topics: alpha-Synuclein; Alzheimer Disease; Antibodies, Bispecific; Brain; Complement C1q; Humans; tau Proteins; Tauopathies

2021
Multiple Neurodegenerative Pathologies in an Alzheimer's Disease Patient Treated with Fornical Deep Brain Stimulation.
    Journal of Alzheimer's disease : JAD, 2021, Volume: 80, Issue:4

    As an established treatment for movement disorders, deep brain stimulation (DBS) has been adapted for the treatment of Alzheimer's disease (AD) by modulating fornix activity. Although it is generally regarded as a safe intervention in patients over 65 years of age, the complex neurophysiology and interconnection within circuits connected to the fornix warrants a careful ongoing evaluation of the true benefit and risk potential of DBS on slowing cognitive decline in AD patients. Here we report on a patient who died long after being implanted with a DBS device who donated her brain for neuropathologic study. The autopsy confirmed multiple proteinopathies including AD-related change, diffuse neocortical Lewy body disease, TDP-43 proteinopathy, and a nonspecific tauopathy. We discuss the possible mechanisms of these overlapping neurodegenerative disorders and caution that future studies of DBS for AD will need to take these findings into consideration.

    Topics: Aged; alpha-Synuclein; Alzheimer Disease; Autopsy; Brain; Deep Brain Stimulation; Female; Humans; Lewy Body Disease; Tauopathies; TDP-43 Proteinopathies

2021
In Vivo Diagnosis of Synucleinopathies: A Comparative Study of Skin Biopsy and RT-QuIC.
    Neurology, 2021, 05-18, Volume: 96, Issue:20

    To determine whether (1) immunofluorescence is a reproducible technique in detecting misfolded α-synuclein in skin nerves and subsequently whether (2) immunofluorescence and real-time quaking-induced conversion (RT-QuIC) (both in skin and CSF) show a comparable in vivo diagnostic accuracy in distinguishing synucleinopathies from non-synucleinopathies in a large cohort of patients.. We prospectively recruited 90 patients fulfilling clinical and instrumental diagnostic criteria for all synucleinopathies variants and non-synucleinopathies (mainly including Alzheimer disease, tauopathies, and vascular parkinsonism or dementia). Twenty-four patients with mainly peripheral neuropathies were used as controls. Patients underwent skin biopsy for immunofluorescence and RT-QuIC; CSF was examined in patients who underwent lumbar puncture for diagnostic purposes. Immunofluorescence and RT-QuIC analysis were made blinded to the clinical diagnosis.. Immunofluorescence showed reproducible results between 2 pairs of neighboring skin samples. Both immunofluorescence and RT-QuIC showed high sensitivity and specificity in discriminating synucleinopathies from non-synucleinopathies and controls but immunofluorescence presented higher diagnostic accuracy. Immunofluorescence presented a good level of agreement with RT-QuIC in both skin and CSF in synucleinopathies.. Both immunofluorescence and RT-QuIC showed high diagnostic accuracy, although immunofluorescence displayed the better value as well as optimal reproducibility; they presented a good level of agreement in synucleinopathies, supporting the use of less invasive tests such as skin immunofluorescence or RT-QuIC instead of CSF RT-QuIC as a diagnostic tool for synucleinopathies.. This study provides Class III evidence that immunofluorescence or RT-QuIC accurately distinguish synucleinopathies from non-synucleinopathies.

    Topics: Aged; alpha-Synuclein; Alzheimer Disease; Female; Fluorescent Antibody Technique; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Parkinson Disease, Secondary; Peripheral Nerves; Protein Aggregates; Reproducibility of Results; Sensitivity and Specificity; Skin; Supranuclear Palsy, Progressive; Synucleinopathies; Tauopathies; TDP-43 Proteinopathies

2021
Deposition of Phosphorylated α-Synuclein and Activation of GSK-3β and PP2A in the PS19 Mouse Model of Tauopathy.
    Journal of neuropathology and experimental neurology, 2021, 09-10, Volume: 80, Issue:8

    The simultaneous accumulation of multiple pathological proteins, such as hyperphosphorylated tau (hp-tau) and phosphorylated α-synuclein (p-αSyn), has been reported in the brains of patients with various neurodegenerative diseases. We previously demonstrated that hp-tau-dependent p-αSyn accumulation was associated with the activation of GSK-3β in the brains of P301L tau transgenic mice. To confirm the effects of another mutant tau on p-αSyn accumulation in vivo, we herein examined the brains of PS19 mice that overexpress human P301S mutant tau. Immunohistochemically, hp-tau and p-αSyn aggregates were detected in the same neuronal cells in the cerebrum and brain stem of aged PS19 mice. A semiquantitative analysis showed a positive correlation between hp-tau and p-αSyn accumulation. Furthermore, an activated form of GSK-3β was detected within cells containing both hp-tau and p-αSyn aggregates in PS19 mice. Western blotting showed a decrease in inactivated PP2A levels in PS19 mice. The present results suggest that the overexpression of human P301S mutant tau induces p-αSyn accumulation that is accompanied by not only GSK-3β, but also PP2A activation in PS19 mice, and highlight the synergic effects between tau and αSyn in the pathophysiology of neurodegenerative diseases that show the codeposition of tau and αSyn.

    Topics: alpha-Synuclein; Animals; Brain; Glycogen Synthase Kinase 3 beta; Mice; Mutation; Presenilins; Protein Phosphatase 2; Tauopathies

2021
Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy.
    Acta neuropathologica communications, 2020, 06-19, Volume: 8, Issue:1

    Neurodegenerative diseases are characterized by the accumulation of specific phosphorylated protein aggregates in the brain, such as hyperphosphorylated tau (hp-tau) in tauopathies and phosphorylated α-synuclein (p-αSyn) in α-synucleinopathies. The simultaneous accumulation of different proteins is a common event in many neurodegenerative diseases. We herein describe the detection of the phosphorylation and dimerization of αSyn and activation of GSK-3β, a major kinase known to phosphorylate tau and αSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-αSyn aggregates in rTg4510 mice, which were suppressed by doxycycline-mediated decreases in mutant tau expression levels. A semi-quantitative analysis revealed a regional correlation between hp-tau and p-αSyn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant αSyn aggregates were found in the region with excessive hp-tau accumulation in rTg4510 mice, and these aggregates were morphologically different from proteinase K-susceptible p-αSyn aggregates. Western blotting revealed decreases in p-αSyn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-αSyn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3β was immunohistochemically detected within cells containing both hp-tau and p-αSyn aggregates. A semi-quantitative analysis revealed that increased GSK-3β activity strongly correlated with hp-tau and p-αSyn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous αSyn by activating GSK-3β in rTg4510 mice. This synergic effect between tau, αSyn, and GSK-3β may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and αSyn.

    Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Humans; Mice, Inbred C57BL; Mice, Transgenic; Phosphorylation; Protein Aggregation, Pathological; tau Proteins; Tauopathies

2020
Association of APOE e2 genotype with Alzheimer's and non-Alzheimer's neurodegenerative pathologies.
    Nature communications, 2020, 09-18, Volume: 11, Issue:1

    The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer's disease (AD), e4, and the major neuroprotective variant, e2. Here we examine the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers in order to examine potential neuroprotective effects. For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. When we separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e4 carriers, not e2 carriers. For multiple fronto-temporal lobar pathologies and tauopathies, e2 was not significantly associated with pathology. In sum, we found that e2 was associated with large but circumscribed protective effects.

    Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Brain; Female; Frontotemporal Lobar Degeneration; Genotype; Humans; Logistic Models; Male; Plaque, Amyloid; Tauopathies

2020
Mixed Brain Pathology Is the Most Common Cause of Cognitive Impairment in the Elderly.
    Journal of Alzheimer's disease : JAD, 2020, Volume: 78, Issue:1

    Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer's disease neuropathologic change (ADNC).. The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney.. 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry.. Hyperphosphorylated τ (HPτ) was seen in 99%, amyloid-β (Aβ) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and α-synuclein (αS) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPτ increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology.. In most (66%) subjects with CI, the cause of impairment was "mixed pathology", i.e., ADNC combined with TDP43, αS, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DM and CaVD, are risk factors for CI but not related to ADNC.

    Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Cardiovascular Diseases; Cognitive Dysfunction; Diabetes Mellitus; Female; Humans; Lewy Bodies; Male; Phosphorylation; tau Proteins; Tauopathies

2020
Ultrasensitive RT-QuIC Seed Amplification Assays for Disease-Associated Tau, α-Synuclein, and Prion Aggregates.
    Methods in molecular biology (Clifton, N.J.), 2019, Volume: 1873

    The abnormal assembly of tau, α-synuclein (αSyn), or prion protein into oligomers and multimers underpins the molecular pathogenesis of multiple neurodegenerative diseases. Such pathological aggregates can often grow by seeded polymerization mechanisms. We and others have taken advantage of these mechanisms to amplify seeding activities in vitro and devise ultrasensitive, specific and quantitative assays for these etiological biomarkers. Real-time quaking-induced conversion (RT-QuIC) assays are performed in multiwell plates with fluorescent readouts, facilitating efficient throughput. Prion RT-QuIC assays on cerebrospinal fluid (CSF) samples are being widely used for antemortem diagnosis of human prion diseases. Recently, we have also described a tau RT-QuIC prototype that has been optimized for Pick disease (with predominant 3R tau pathology) that detects 3R tau seeds in postmortem CSF, and brain tissue dilutions as extreme as a billion-fold. αSyn RT-QuIC prototypes have also been developed, providing ~92% diagnostic sensitivity and 100% specificity for Parkinson's disease and dementia with Lewy bodies using antemortem CSF. Here we provide detailed protocols for our 3R tau and αSyn RT-QuIC assays and refer the reader to published up-to-date protocols for prion RT-QuIC assays (Orru et al. Methods Mol Biol 1658:185-203, 2017; Schmitz et al. Nat Protoc 11:2233-2242, 2016).

    Topics: alpha-Synuclein; Animals; Autopsy; Biological Assay; Brain Chemistry; Cloning, Molecular; Escherichia coli; Gene Expression; Humans; Mice; Prion Diseases; Prion Proteins; Proteostasis Deficiencies; Recombinant Proteins; Software; tau Proteins; Tauopathies

2019
The toxin MPTP generates similar cognitive and locomotor deficits in hTau and tau knock-out mice.
    Brain research, 2019, 05-15, Volume: 1711

    Parkinson's disease (PD) is characterized by motor deficits, although cognitive disturbances are frequent and have been noted early in the disease. The main pathological characteristics of PD are the loss of dopaminergic neurons and the presence of aggregated α-synuclein in Lewy bodies of surviving cells. Studies have also documented the presence of other proteins within Lewy bodies, particularly tau, a microtubule-associated protein implicated in a wide range of neurodegenerative diseases, including Alzheimer's disease (AD). In AD, tau pathology correlates with cognitive dysfunction, and tau mutations have been reported to lead to dementia associated with parkinsonism. However, the role of tau in PD pathogenesis remains unclear. To address this question, we induced parkinsonism by injecting the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in hTau mice, a mouse model of tauopathy expressing human tau, and a mouse model knock-out for tau (TKO). We found that although MPTP impaired locomotion (gait analysis) and cognition (Barnes maze), there were no discernable differences between hTau and TKO mice. MPTP also induced a slight but significant increase in tau phosphorylation (Thr205) in the hippocampus of hTau mice, as well as a significant decrease in the soluble and insoluble tau fractions that correlated with the loss of dopaminergic neurons in the brainstem. Overall, our findings suggest that, although MPTP can induce an increase in tau phosphorylation at specific epitopes, tau does not seem to causally contribute to cognitive and locomotor deficits induced by this toxin.

    Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Alzheimer Disease; Animals; Brain; Cognition; Disease Models, Animal; Dopaminergic Neurons; Female; Hippocampus; Humans; Locomotion; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Parkinson Disease; Phosphorylation; tau Proteins; Tauopathies

2019
Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.
    Brain : a journal of neurology, 2018, 07-01, Volume: 141, Issue:7

    Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate

    Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Apolipoprotein E4; DNA-Binding Proteins; Female; Humans; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Pick Disease of the Brain; Prevalence; Supranuclear Palsy, Progressive; tau Proteins; Tauopathies; TDP-43 Proteinopathies

2018
Influence of Early Life Lead (Pb) Exposure on α-Synuclein, GSK-3β and Caspase-3 Mediated Tauopathy: Implications on Alzheimer's Disease.
    Current Alzheimer research, 2018, Volume: 15, Issue:12

    Previously we have shown that developmental exposure to the heavy metal lead (Pb) resulted in latent cognitive impairment, upregulation of biomarkers and pathology associated with both the tau and amyloid pathways, however, the impact on Alpha Synuclein (α-Syn) and its relationship to these pathways and their connection to cognitive performance warrant further elucidation.. The present study determined the impact of developmental Pb exposure on the α-Syn pathways in a mouse model knock-out (KO) for murine tau gene and in differentiated human neuroblastoma SHSY5Y cell line exposed to a series of Pb concentrations.. Western blot analysis and RT-PCR were used to assess the levels of intermediates in the tau and α-Syn pathways following postnatal Pb exposure on aged mice lacking tau gene and in differentiated SHSY5Y cells on day 3 and day 6 after the Pb exposure had ceased.. Early life Pb exposure is accompanied by latent up-regulation in α-Syn in these mice. Furthermore, prior exposure to Pb in-vitro also resulted in an increase in α-Syn, its phosphorylated forms, as well as an increase in glycogen synthase kinase 3β (GSK-3β) and Caspase-3.. An environmental agent can act as a latent inducer of both α-Syn and associated kinases that are involved in tau hyperphosphorylation and may allude to the interactive nature of these two neurodegenerative pathways.

    Topics: alpha-Synuclein; Animals; Caspase 3; Cell Line, Tumor; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Green Fluorescent Proteins; Humans; Lead; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroblastoma; tau Proteins; Tauopathies; Up-Regulation

2018
Deposition of Phosphorylated α-Synuclein in the rTg4510 Mouse Model of Tauopathy.
    Journal of neuropathology and experimental neurology, 2018, 10-01, Volume: 77, Issue:10

    The accumulation of specific phosphorylated protein aggregates in the brain is a hallmark of severe neurodegenerative disorders. Specifically, hyperphosphorylated tau (hp-tau) accumulates in Alzheimer disease, frontotemporal dementia with Parkinsonism linked to chromosome 17, and progressive supranuclear palsy; furthermore, phosphorylated α-synuclein (p-αSyn) accumulates in Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. Moreover, codeposition of different pathological protein aggregates is common in the brains of individuals with neurodegenerative diseases. In the present report, we describe the detection of p-αSyn aggregates in the brain of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed that hp-tau and p-αSyn aggregates were found within the same neuronal cells in rTg4510 mice and increased with age. Moreover, semiquantitative analysis revealed a significant regional correlation between hp-tau and p-αSyn accumulation. These results indicate that endogenous mouse αSyn protein is phosphorylated and accumulates with hp-tau aggregation in neurons and suggest that the overexpression of human P301L mutant tau may enhance endogenous αSyn phosphorylation and aggregation via a similar hyperphosphorylation mechanism in vivo. This synergic effect between tau and αSyn accumulation may exacerbate the pathology of several neurodegenerative disorders that show a cooccurrence of hp-tau and p-αSyn aggregation.

    Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphorylation; Protein Aggregation, Pathological; tau Proteins; Tauopathies

2018
Human cyclophilin 40 unravels neurotoxic amyloids.
    PLoS biology, 2017, Volume: 15, Issue:6

    The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer's disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids.

    Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Animals; Blotting, Western; Brain; Cognition Disorders; Cyclophilins; Cyclosporine; Disease Models, Animal; Female; HEK293 Cells; Humans; Male; Mice, Transgenic; Microscopy, Electron, Transmission; Neurodegenerative Diseases; Peptidyl-Prolyl Isomerase F; Protein Aggregates; Protein Aggregation, Pathological; tau Proteins; Tauopathies

2017
Neuronal Loss and Α-Synuclein Pathology in the Superior Colliculus and Its Relationship to Visual Hallucinations in Dementia with Lewy Bodies.
    The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 2017, Volume: 25, Issue:6

    Patients with dementia with Lewy bodies (DLB) often experience visual hallucinations, which are related to decreased quality of life for patients and increased caregiver distress. The pathologic changes that contribute to visual hallucinations are not known, but several hypotheses implicate deficient attentional processing. The superior colliculus has a role in visual attention and planning eye movements and has been directly implicated in several models of visual hallucinations. Therefore, the present study sought to identify neurodegenerative changes that may contribute to hallucinations in DLB.. Postmortem superior colliculus tissue from 13 comparison, 10 DLB, and 10 Alzheimer disease (AD) cases was evaluated using quantitative neuropathologic methods.. α-Synuclein and tau deposition were more severe in deeper layers of the superior colliculus. DLB cases had neuronal density reductions in the stratum griseum intermedium, an important structure in directing attention toward visual targets. In contrast, neuronal density was reduced in all laminae of the superior colliculus in AD.. These findings suggest that regions involved in directing attention toward visual targets are subject to neurodegenerative changes in DLB. Considering several hypotheses of visual hallucinations implicating dysfunctional attention toward external stimuli, these findings may provide evidence of pathologic changes that contribute to the manifestation of visual hallucinations in DLB.

    Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Case-Control Studies; Cell Count; Female; Hallucinations; Humans; Lewy Body Disease; Male; Middle Aged; Nerve Degeneration; Superior Colliculi; Tauopathies

2017
Editorial overview: Neurobiology of disease.
    Current opinion in neurobiology, 2016, Volume: 36

    Topics: alpha-Synuclein; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Brain; C9orf72 Protein; Chronic Pain; Epilepsy; Genome-Wide Association Study; Humans; Mental Disorders; Neuralgia; Neurobiology; Neurodegenerative Diseases; Parkinson Disease; Proteins; tau Proteins; Tauopathies

2016
Altered Proteins in the Aging Brain.
    Journal of neuropathology and experimental neurology, 2016, Volume: 75, Issue:4

    We assessed the prevalence of common altered brain proteins in 296 cognitively unimpaired subjects ranging from age 50 to 102 years. The incidence and the stage of hyperphosphorylated-τ (HPτ), β-amyloid, α-synuclein (αS), and transactive response DNA (TDP) binding protein 43 (TDP43)-immunoreactivity (-IR) increased with age. HPτ-IR was observed in 98% of the subjects; the locus coeruleus was solely affected in 46%, and 79% of the subjects were in Braak stages a to II. β-Amyloid was seen in 47% of subjects and the Thal phase correlated with the HPτ Braak stage and age. Intermediate Alzheimer disease-related pathology (ADRP) was seen in 12%; 52% of the subjects with HPτ-IR fulfilled criteria for definite primary age-related tauopathy (PART). The incidence of concomitant pathology (αS, TDP43) did not differ between those with PART and those with ADRP but the former were younger. TDP43-IR was observed in 36%; the most frequently affected region was the medulla; αS-IR was observed in 19% of subjects. In 41% of the subjects from 80 to 89 years at death, 3 altered proteins were seen in the brain. Thus, altered proteins are common in the brains of cognitively unimpaired aged subjects; this should be considered while developing diagnostic biomarkers, particularly for identifying subjects at early stages of neurodegenerative diseases.

    Topics: Age Factors; Aged; Aged, 80 and over; Aging; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; DNA-Binding Proteins; Female; Humans; Longitudinal Studies; Male; Middle Aged; Phosphorylation; tau Proteins; Tauopathies

2016
Neurodegeneration in tauopathies and synucleinopathies.
    Revue neurologique, 2016, Volume: 172, Issue:11

    While increasing life expectancy is a major achievement, the global aging of societies raises a number of medical issues, such as the development of age-related disorders, including neurodegenerative diseases. The three main disease groups constituting the majority of neurodegenerative diseases are tauopathies, alpha-synucleinopathies and diseases due to repetitions of glutamine (including Huntington's disease). In each neurodegenerative disease, the accumulation of one or more aggregated proteins has been identified as the molecular signature of the disease (as seen, for example, in Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis and frontotemporal dementia). The etiology of neurodegenerative diseases is often multifactorial, and the known risk factors include, in addition to genetic polymorphisms and age, some other possible causes, such as certain immune and metabolic conditions, endocrine pathologies, gender, socioeconomic or professional status, oxidative stress or inflammation, vitamin deficiencies and environmental factors (chemical exposure, metals). However, innovative strategies to elaborate suitable diagnostic and therapeutic approaches (aiming to at least delay or possibly even reverse disease progression) require further knowledge of the genetic and adaptive immunological characteristics of neurodegenerative diseases.

    Topics: alpha-Synuclein; Brain; Cytoskeleton; Humans; Inclusion Bodies; Lewy Body Disease; Nerve Degeneration; Neurodegenerative Diseases; Parkinsonian Disorders; Tauopathies

2016
Shared and Distinct Patterns of Oligodendroglial Response in α-Synucleinopathies and Tauopathies.
    Journal of neuropathology and experimental neurology, 2016, 12-01, Volume: 75, Issue:12

    Pathological protein deposits in oligodendroglia are common but variable features of various neurodegenerative conditions. To evaluate oligodendrocyte response in neurodegenerative diseases (NDDs) with different extents of oligodendroglial protein deposition we performed immunostaining for tubulin polymerization-promoting protein p25α (TPPP/p25α), α-synuclein (α-syn), phospho-tau, ubiquitin, myelin basic protein, and the microglial marker HLA-DR. We investigated cases of multiple system atrophy ([MSA] n = 10), Lewy body disease ([LBD] n = 10), globular glial tauopathy ([GGT] n = 7) and progressive supranuclear palsy ([PSP] n = 10). Loss of nuclear TPPP/p25α immunoreactivity correlated significantly with the degree of microglial reaction and loss of myelin basic prtein density as a marker of tract degeneration. This was more prominent in MSA and GGT, which, together with enlarged cytoplasmic TPPP/p25α immunoreactivity and inclusion burden allowed these disorders to be grouped as predominant oligodendroglial proteinopathies. However, distinct features, ie more colocalization of α-syn than tau with TPPP/p25α, more obvious loss of oligodendrocyte density in MSA, but more prominent association of tau protein inclusions in GGT to loss of nuclear TPPP/p25α immunoreactivity, were also recognized. In addition, we observed previously underappreciated oligodendroglial α-synuclein pathology in the pallidothalamic tract in LBD. Our study demonstrates common and distinct aspects of oligodendroglial involvement in the pathogenesis of diverse NDDs.

    Topics: Aged; Aged, 80 and over; alpha-Synuclein; Brain; Female; Humans; Male; Middle Aged; Nerve Tissue Proteins; Neurodegenerative Diseases; Oligodendroglia; tau Proteins; Tauopathies

2016
A Naturally Occurring Bovine Tauopathy Is Geographically Widespread in the UK.
    PloS one, 2015, Volume: 10, Issue:6

    Many human neurodegenerative diseases are associated with hyperphosphorylation and widespread intra-neuronal and glial associated aggregation of the microtubule associated protein tau. In contrast, animal tauopathies are not reported with only senescent animals showing inconspicuous tau labelling of fine processes albeit significant tau aggregation may occur in some experimental animal disease. Since 1986, an idiopathic neurological condition of adult cattle has been recognised in the UK as a sub-set of cattle slaughtered as suspect bovine spongiform encephalopathy cases. This disorder is characterised by brainstem neuronal chromatolysis and degeneration with variable hippocampal sclerosis and spongiform change. Selected cases of idiopathic brainstem neuronal chromatolysis (IBNC) were identified from archive material and characterised using antibodies specific to several tau hyperphosphorylation sites or different isoforms of the tau microtubule binding region. Labelling was also carried out for alpha synuclein, ubiquitin, TDP43, Aβ 1-42, Aβ 1-40. Widespread tau labelling was identified in all IBNC brains examined and with each of seven tau antibodies recognising different hyperphosphorylated sites. Labelling with each antibody was associated with dendrites, neuronal perikarya and glia. Thus IBNC is a sporadic, progressive neurological disease predominantly affecting aged cattle that occurs throughout the UK and is associated with hyperphosphorylation of tau, a rare example of a naturally-occurring tauopathy in a non-primate species. Secondary accumulation of alpha synuclein and ubiquitin was also present. The neuropathology does not precisely correspond with any human tauopathy. The cause of IBNC remains undetermined but environmental factors and exposure to agrochemicals needs to be considered in future aetiological investigations.

    Topics: alpha-Synuclein; Animals; Brain; Cattle; Cattle Diseases; Encephalopathy, Bovine Spongiform; Hippocampus; Humans; Incidence; Neuroglia; Neurons; Protein Isoforms; tau Proteins; Tauopathies; United Kingdom

2015
Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations.
    Brain : a journal of neurology, 2015, Volume: 138, Issue:Pt 11

    Tauopathies, such as Alzheimer's disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are present in the adult human brain and they differ by the presence of 3(3R) or 4(4R) C-terminal repeats. Only the shortest 3R isoform is present in foetal brain. MAPT mutations found in human disease affect tau binding to microtubules or the 3R:4R isoform ratio by altering exon 10 splicing. We have differentiated neurons from induced pluripotent stem cells derived from fibroblasts of controls and patients with N279K and P301L MAPT mutations. Induced pluripotent stem cell-derived neurons recapitulate developmental tau expression, showing the adult brain tau isoforms after several months in culture. Both N279K and P301L neurons exhibit earlier electrophysiological maturation and altered mitochondrial transport compared to controls. Specifically, the N279K neurons show abnormally premature developmental 4R tau expression, including changes in the 3R:4R isoform ratio and AT100-hyperphosphorylated tau aggregates, while P301L neurons are characterized by contorted processes with varicosity-like structures, some containing both alpha-synuclein and 4R tau. The previously unreported faster maturation of MAPT mutant human neurons, the developmental expression of 4R tau and the morphological alterations may contribute to disease development.

    Topics: Adult; Aged; alpha-Synuclein; Case-Control Studies; Cell Line; Cells, Cultured; Female; Gene Expression Regulation, Developmental; Humans; Immunohistochemistry; Induced Pluripotent Stem Cells; Infant, Newborn; Male; Microscopy, Confocal; Microtubules; Middle Aged; Neurons; Patch-Clamp Techniques; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; tau Proteins; Tauopathies

2015
Sensitive Detection of Proteopathic Seeding Activity with FRET Flow Cytometry.
    Journal of visualized experiments : JoVE, 2015, Dec-08, Issue:106

    Increasing evidence supports transcellular propagation of toxic protein aggregates, or proteopathic seeds, as a mechanism for the initiation and progression of pathology in several neurodegenerative diseases, including Alzheimer's disease and the related tauopathies. The potentially critical role of tau seeds in disease progression strongly supports the need for a sensitive assay that readily detects seeding activity in biological samples. By combining the specificity of fluorescence resonance energy transfer (FRET), the sensitivity of flow cytometry, and the stability of a monoclonal cell line, an ultra-sensitive seeding assay has been engineered and is compatible with seed detection from recombinant or biological samples, including human and mouse brain homogenates. The assay employs monoclonal HEK 293T cells that stably express the aggregation-prone repeat domain (RD) of tau harboring the disease-associated P301S mutation fused to either CFP or YFP, which produce a FRET signal upon protein aggregation. The uptake of proteopathic tau seeds (but not other proteins) into the biosensor cells stimulates aggregation of RD-CFP and RD-YFP, and flow cytometry sensitively and quantitatively monitors this aggregation-induced FRET. The assay detects femtomolar concentrations (monomer equivalent) of recombinant tau seeds, has a dynamic range spanning three orders of magnitude, and is compatible with brain homogenates from tauopathy transgenic mice and human tauopathy subjects. With slight modifications, the assay can also detect seeding activity of other proteopathic seeds, such as α-synuclein, and is also compatible with primary neuronal cultures. The ease, sensitivity, and broad applicability of FRET flow cytometry makes it useful to study a wide range of protein aggregation disorders.

    Topics: alpha-Synuclein; Alzheimer Disease; Animals; Biosensing Techniques; Brain; Brain Chemistry; Flow Cytometry; Fluorescence Resonance Energy Transfer; HEK293 Cells; Humans; Mice; Mice, Transgenic; tau Proteins; Tauopathies

2015
Early Stage of Progressive Supranuclear Palsy: A Neuropathological Study of 324 Consecutive Autopsy Cases.
    Journal of Nippon Medical School = Nippon Ika Daigaku zasshi, 2015, Volume: 82, Issue:6

    Diagnosing clinical progressive supranuclear palsy (PSP) is challenging. We hypothesize that there are more cases of pathological PSP than have been clinically identified, but its diagnosis is challenging because the initial lesions and progression of PSP have not yet been clarified. The purpose of our study was to clarify the incidence of PSP in consecutive autopsy cases and identify pathological characteristics of early PSP. We investigated 324 consecutive autopsy patients from a general geriatric hospital (age, mean±SD=82.5±8.7 years). Paraffin sections of the midbrain were immunostained with anti 4-repeat tau antibodies (RD4). We selected cases showing RD4-positive neurofibrillary tangles and tufted astrocytes in the midbrain sections. Then, we used anti-phosphorylated tau antibody to immunostain sections from the basal ganglia, subthalamic nucleus, midbrain, pons, medulla, and cerebellum. Of the 324 patients, 35 had RD4-positive structures in the midbrain. From these 35 cases, we excluded those for which autopsies confirmed definite PSP (n=5) and cases of corticobasal degeneration (n=1), Alzheimer's disease (n=11), dementia of grain (n=10), and neurofibrillary tangles predominant forms of senile dementia (n=2), leaving 8 cases. We diagnosed these 8 cases as pure PSP-type tauopathy. Pure PSP-type tauopathy was detected in 2.5% of the consecutive autopsy cases, and this incidence was 1.6 times greater than that of neuropathologically definite PSP. This pure PSP-type tauopathy likely indicates preclinical stages of PSP. Furthermore, the novel neuropathological finding, which we term "preclinical PSP," is unique and has not previously been reported. In order to elucidate the causes and pathological mechanisms of PSP, preclinical PSP should be investigated further.

    Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Male; Mesencephalon; Middle Aged; Neurofibrillary Tangles; Severity of Illness Index; Supranuclear Palsy, Progressive; tau Proteins; Tauopathies

2015
CSF α-synuclein and UCH-L1 levels in Parkinson's disease and atypical parkinsonian disorders.
    Parkinsonism & related disorders, 2014, Volume: 20, Issue:4

    There is an unmet need for biomarkers for Parkinson's disease (PD) and atypical parkinsonian disorders (APD). α-Synuclein, linked to the pathogenesis of PD, is a promising biomarker candidate in need of further investigation. The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin proteasome system which seems to be disturbed in PD, may also be involved in the pathogenesis of this disorder.. We investigated cerebrospinal fluid (CSF) α-synuclein and UCH-L1 levels from 22 healthy controls, 52 patients with PD, 34 with multiple system atrophy (MSA), 32 with progressive supranuclear palsy, and 12 with corticobasal degeneration.. α-Synuclein levels were significantly decreased in PD and in MSA compared with controls, and in synucleinopathies compared with tauopathies. UCH-L1 levels were significantly decreased in PD, MSA as well as PSP compared with controls, and in PD compared with APD (p < 0.001). Both markers discriminated PD well from controls (p < 0.0001; area under the curve [AUC] = 0.82 and 0.89, respectively). Additionally, CSF α-synuclein separated patients with synucleinopathies from those with tauopathies (p = 0.015; AUC = 0.63), whereas CSF UCH-L1 discriminated between PD and APD (p = 0.0003; AUC = 0.69). Interestingly, α-synuclein and UCH-L1 levels were strongly correlated in PD and synucleinopathies, and weakly in tauopathies. No correlation was found in controls.. CSF levels of α-synuclein and UCH-L1 show distinct patterns in parkinsonian syndromes. Their combined determination may be useful in the differential diagnosis of parkinsonian disorders and provide key to understanding their pathoetiology and clinical course. Further large studies are needed to validate our findings.

    Topics: Aged; alpha-Synuclein; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive; Tauopathies; Ubiquitin Thiolesterase

2014
Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer's disease and tauopathies.
    Acta neuropathologica, 2014, Volume: 128, Issue:5

    Neuronal insulin signaling abnormalities have been associated with Alzheimer's disease (AD). However, the specificity of this association and its underlying mechanisms have been unclear. This study investigated the expression of abnormal serine phosphorylation of insulin receptor substrate 1 (IRS1) in 157 human brain autopsy cases that included AD, tauopathies, α-synucleinopathies, TDP-43 proteinopathies, and normal aging. IRS1-pS(616), IRS1-pS(312) and downstream target Akt-pS(473) measures were most elevated in AD but were also significantly increased in the tauopathies: Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Double immunofluorescence labeling showed frequent co-expression of IRS1-pS(616) with pathologic tau in neurons and dystrophic neurites. To further investigate an association between tau and abnormal serine phosphorylation of IRS1, we examined the presence of abnormal IRS1-pS(616) expression in pathological tau-expressing transgenic mice and demonstrated that abnormal IRS1-pS(616) frequently co-localizes in tangle-bearing neurons. Conversely, we observed increased levels of hyperphosphorylated tau in the high-fat diet-fed mouse, a model of insulin resistance. These results provide confirmation and specificity that abnormal phosphorylation of IRS1 is a pathological feature of AD and other tauopathies, and provide support for an association between insulin resistance and abnormal tau as well as amyloid-β.

    Topics: Age Factors; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Analysis of Variance; Animals; Brain; Diet, High-Fat; DNA-Binding Proteins; Female; Humans; Insulin Receptor Substrate Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Phosphorylation; Serine; tau Proteins; Tauopathies; TDP-43 Proteinopathies

2014
Binding of the PET radiotracer [¹⁸F]BF227 does not reflect the presence of alpha-synuclein aggregates in transgenic mice.
    Current Alzheimer research, 2014, Volume: 11, Issue:10

    Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many neurodegenerative diseases, collectively termed synucleinopathies. There is currently no pre-mortem diagnosis tool for these diseases. Although some compounds have been described as potential ligands for α-syn aggregates, no specific PET radiotracer of aggregated α-syn is currently available. Recently, [(18)F]BF227 has been proposed as an α-syn PET radiotracer in the absence of other specific candidates. We proposed here, for the first time, to use this radiotracer in an accelerated mouse model of synucleinopathy presenting α-syn depositions in brainstem and thalamus. Our in vivo and in vitro studies showed that [(18)F]BF227 does not bind to α-syn aggregates. These results highlight the fact that [(18)F]BF227 PET has no suitable characteristics for monitoring this experimental synucleinopathy, justifying the need to develop alternative α-syn PET radiotracers.

    Topics: alpha-Synuclein; Animals; Benzoxazoles; Brain Stem; Disease Models, Animal; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Positron-Emission Tomography; Radioligand Assay; Tauopathies; Thalamus; Thiazoles

2014
The glial marker YKL-40 is decreased in synucleinopathies.
    Movement disorders : official journal of the Movement Disorder Society, 2013, Volume: 28, Issue:13

    Microglia are resident immunosurveillant cells in the central nervous system, and astrocytes are important for blood flow, plasticity, and neurotransmitter regulation. The aim of this study was to investigate whether astrocyte and microglial activation, estimated through markers in cerebrospinal fluid and serum, differed between synucleinopathies, tauopathies, and controls.. We analyzed the glial activation markers YKL-40 and soluble CD14 in serum and cerebrospinal fluid from 37 controls, 50 patients with Parkinson's disease (PD), and 79 P+ patients (those with progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy).. Cerebrospinal fluid levels of YKL-40 were decreased significantly in patients who had PD compared with controls (P < 0.05), patients who had multiple system atrophy (P < 0.01), and patients who had tauopathies (P < 0.0001). In addition, cerebrospinal fluid levels of YKL-40 were significantly lower in patients who had synucleinopathies than in those who had tauopathies (P < 0.0001).. The decreased cerebrospinal fluid levels of YKL-40 suggest that glial activation is reduced in the brains of patients who have Parkinson's disease and synucleinopathies compared with patients who have tauopathies and controls.

    Topics: Adipokines; Aged; alpha-Synuclein; Analysis of Variance; Basal Ganglia Diseases; Chitinase-3-Like Protein 1; Female; Humans; Lectins; Lipopolysaccharide Receptors; Male; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease; Supranuclear Palsy, Progressive; Tauopathies

2013
Neurodegenerative disease: can synucleinopathy and tauopathy be identified during life?
    Nature reviews. Neurology, 2013, Volume: 9, Issue:8

    Topics: alpha-Synuclein; Humans; Neurodegenerative Diseases; Tauopathies

2013
Wild type and P301L mutant Tau promote neuro-inflammation and α-Synuclein accumulation in lentiviral gene delivery models.
    Molecular and cellular neurosciences, 2012, Volume: 49, Issue:1

    Neurodegeneration involves multiple pathogenic proteins, including Tau, Aβ, TDP-43 and α-Synuclein, but there is little information how these pathogenic proteins interact. We cloned human wild type 4 repeat Tau (Tau(wt)) and mutant Tau(P301L) into a lentivirus and performed stereotaxic injection into the rat motor cortex to examine Tau modification, neuro-inflammation and changes of other proteins associated with neurodegeneration. Tau(P301L) was associated with more phosphorylation of Tau, including Thr 181 and Ser 262 residues and resulted in more aggregation. Both forms of Tau expression increased glycogen synthase kinase-3 (GSK-3) activity, polo-like kinase-2 (PLK2) levels and decreased protein phosphatase activity, but had no effects on casein kinase-1 (CK1). No changes were observed in glial fibrillary acidic protein (GFAP) staining with either Tau(wt) or Tau(P301L), but both caused microglial changes and higher interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels. Tau(wt) and Tau(P301L) increased the levels of endogenous α-Synuclein, but not β-amyloid precursor protein (βAPP) or Tar-DNA binding protein (TDP-43). The levels of phosphorylated Ser-129 α-Synuclein (p-Ser129) were also increased with Tau(wt) and Tau(P301L) expressing animals. These data suggest that Tau(wt) and Tau(P301L) alter kinase activities, but they differentially induce inflammation, Tau modification and α-Synuclein phosphorylation. This change of α-Synuclein in Tau gene transfer models suggests that Tau pathology may lead to α-Synuclein modification in neurodegenerative diseases.

    Topics: alpha-Synuclein; Animals; DNA-Binding Proteins; Gene Transfer Techniques; Glycogen Synthase Kinase 3; Inflammation; Interleukin-6; Lentivirus; Models, Animal; Motor Cortex; Phosphorylation; Rats; Rats, Sprague-Dawley; tau Proteins; Tauopathies

2012
Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways.
    PloS one, 2012, Volume: 7, Issue:1

    SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau.

    Topics: alpha-Synuclein; Animals; Autophagy; Case-Control Studies; Corpus Striatum; Down-Regulation; Fungicides, Industrial; Herbicides; Humans; Male; Maneb; Mice; Mice, Inbred C57BL; Paraquat; Parkinsonian Disorders; Proteasome Endopeptidase Complex; Signal Transduction; Tauopathies

2012
Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson's disease.
    The European journal of neuroscience, 2011, Volume: 33, Issue:9

    Although clinically distinct diseases, tauopathies and synucleinopathies share a common genesis and mechanisms, leading to overlapping degenerative changes within neurons. In human postmortem striatum of Parkinson's disease (PD) and PD with dementia, we have recently described elevated levels of tauopathy, indexed as increased hyperphosphorylated Tau (p-Tau). Here we assessed tauopathy in striatum of a transgenic animal model of PD, overexpressing human α-synuclein under the platelet-derived growth factor promoter. At 11 months of age, large and progressive increases in p-Tau in transgenic mice, hyperphosphorylated at sites reminiscent of Alzheimer's disease, were noted, along with elevated levels of α-synuclein and glycogen synthase kinase 3β phosphorylated at Tyr216 (p-GSK-3β), a major kinase involved in the hyperphosphorylation of Tau. Differential Triton X-100 extraction of striata showed the presence of aggregated α-synuclein in the transgenic mice, along with p-Tau and p-GSK-3β, which was also confirmed through immunohistochemistry. After p-Tau formation, both Tau and microtubule-associated protein 1 (MAP1) dissociated from the cytoskeleton, consistent with the diminished ability of these cytoskeleton-binding proteins to bind microtubules. Increases in free tubulin and actin were also noted, indicative of cytoskeleton remodeling and destabilization. In vivo magnetic resonance imaging of the transgenic animals showed a reduction in brain volume of transgenic mice, indicating substantial atrophy. From immunohistochemical studies, α-synuclein, p-Tau and p-GSK-3β were found to be overexpressed and co-localized in large inclusion bodies, reminiscent of Lewy bodies. The elevated state of tauopathy seen in these platelet-derived growth factor-α-synuclein mice provides further confirmation that PD may be a tauopathic disease.

    Topics: Aged; Aged, 80 and over; alpha-Synuclein; Animals; Corpus Striatum; Cytoskeleton; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Middle Aged; Neurons; Parkinson Disease; Phosphorylation; Platelet-Derived Growth Factor; Protein Conformation; tau Proteins; Tauopathies

2011
Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease.
    BMC neuroscience, 2011, Aug-03, Volume: 12

    α-synuclein [α-Syn]-mediated activation of GSK-3β leading to increases in hyperphosphorylated Tau has been shown by us to occur in striata of Parkinson's diseased [PD] patients and in animal models of PD. In Alzheimer's disease, tauopathy exists in several brain regions; however, the pattern of distribution of tauopathy in other brain regions of PD or in animal models of PD is not known. The current studies were undertaken to analyze the distribution of tauopathy in different brain regions in a widely used mouse model of PD, the α-Syn overexpressing mouse.. High levels of α-Syn levels were seen in the brain stem, with a much smaller increase in the frontal cortex; neither cerebellum nor hippocampus showed any overexpression of α-Syn. Elevated levels of p-Tau, hyperphosphorylated at Ser202, Ser262 and Ser396/404, were seen in brain stem, with lower levels seen in hippocampus. In both frontal cortex and cerebellum, increases were seen only in p-Ser396/404 Tau, but not in p-Ser202 and p-Ser262. p-GSK-3β levels were not elevated in any of the brain regions, although total GSK-3β was elevated in brain stem. p-p38MAPK levels were unchanged in all brain regions examined, while p-ERK levels were elevated in brain stem, hippocampus and cerebellum, but not the frontal cortex. p-JNK levels were increased in brain stem and cerebellum but not in the frontal cortex or hippocampus. Elevated levels of free tubulin, indicating microtubule destabilization, were seen only in the brain stem.. Our combined data suggest that in this animal model of PD, tauopathy, along with microtubule destabilization, exists primarily in the brain stem and striatum, which are also the two major brain regions known to express high levels of α-Syn and undergo the highest levels of degeneration in human PD. Thus, tauopathy in PD may have a very restricted pattern of distribution.

    Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Multiple System Atrophy; Parkinsonian Disorders; Tauopathies; Tissue Distribution; Up-Regulation

2011
Burden of neurodegenerative diseases in a cohort of medical examiner subjects.
    Journal of forensic sciences, 2010, Volume: 55, Issue:3

    Here we report studies of the burden of neurodegenerative neuropathologies in a cohort of Medical Examiner (ME) subjects from the County of Santa Clara (California) to determine if this unique population of decedents manifested evidence of neurodegeneration that might underlie causes of death seen in an ME practice. We found that 13% of the brains from ME cases showed significant tau pathology, including 55% of those 65 years old and older and 63% of those 70 years old and older. The histochemical and immunohistochemical findings were consistent with Alzheimer's disease (AD) in 7 subjects and frontotemporal lobar degeneration (FTLD) tauopathy type in six cases. There were no cases of Parkinson's disease, dementia with Lewy Bodies or other neurodegenerative conditions. Our study suggests that decedents >65 years of age in an ME practice are afflicted by common causes of dementia such as AD and FTLD which could contribute wholly or in part to their causes of death.

    Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Atrophy; Benzothiazoles; Brain; Brain Edema; Cohort Studies; Coroners and Medical Examiners; Female; Forensic Pathology; Frontotemporal Lobar Degeneration; Humans; Hygiene; Ill-Housed Persons; Immunohistochemistry; Male; Malnutrition; Middle Aged; Neurofibrillary Tangles; Neuropil Threads; Plaque, Amyloid; Staining and Labeling; Tauopathies; Thiazoles; Young Adult

2010
Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia.
    Experimental neurology, 2010, Volume: 225, Issue:1

    Parkinson's disease (PD), a progressive neurodegenerative disease, results in abnormal accumulation of insoluble alpha-synuclein (alpha-Syn) in dopaminergic neurons. Here we examined tauopathic changes and the alpha-Syn/p-GSK-3beta/proteasome pathway in postmortem striata and inferior frontal gyri (IFG) from patients with PD and PD with dementia (PDD). In both PD and PDD, alpha-Syn levels were high, especially the insoluble form of this protein; in PDD, insoluble alpha-Syn levels were persistently higher than PD across both brain regions. Levels of p-GSK-3beta phosphorylated at Tyr 216, which hyperphosphorylates Tau to produce toxic pathological forms of p-Tau, were higher in striata of both PD and PDD compared to controls, but were unaltered in IFG. While proteasomal activity was unchanged in striatum of PD and PDD, such activity was diminished in the IFG of both PD and PDD. A decrease in 19S subunit of the proteasomes was seen in IFG of PDD, while lower levels of 20S subunits were seen in striatum and IFG of both PD and PDD patients. Parkin levels were similar in PD and PDD, suggesting lack of involvement of this protein. Most interestingly, tauopathic changes were noted only in striatum of PD and PDD, with increased hyperphosphorylation seen at Ser262 and Ser396/404; increases in Ser202 levels were seen only in PD but not in PDD striatum. We were unable to detect any tauopathy in IFG in either PD or PDD despite increased levels of alpha-Syn, and decreased proteasomal activity, and is probably due to lack of increase in p-GSK-3beta in IFG. Unlike Alzheimer's disease where tauopathy is more globally observed in diverse brain regions, our data demonstrates restricted expression of tauopathy in brains of PD and PDD, probably limited to dopaminergic neurons of the nigrostriatal region.

    Topics: alpha-Synuclein; Brain; Corpus Striatum; Dementia; Dopamine; Female; Humans; Male; Neurons; Parkinson Disease; tau Proteins; Tauopathies; Up-Regulation

2010
Parkin attenuates wild-type tau modification in the presence of beta-amyloid and alpha-synuclein.
    Journal of molecular neuroscience : MN, 2009, Volume: 37, Issue:1

    Changes in tau (tau) metabolism comprise important pathological landmarks in the tauopathies with parkinsonism as well as Parkinson's disease and Alzheimer's disease. Mutations in the parkin gene are associated with Parkinson's disease. Deposits of amyloid proteins, including Abeta and alpha-synuclein coexist in the brains of patients with dementia with Lewy bodies; however, it is not known how either of them interacts with tau to provoke neurofibrillary tangle formation across the tauopathies. Here, we show a role for parkin against tau pathology in the presence of intracellular Abeta or alpha-synuclein. Parkin attenuates four-repeat human tau, but not mutant P301L, hyperphosphorylation in the presence of intracellular Abeta(1-42), or alpha-synuclein and decreases GSK-3beta activity in amyloid-stressed M17 human neuroblastoma cells. These data suggest that parkin may counteract the alteration of tau metabolism in certain neurodegenerative diseases with tau cytopathy and parkinsonism.

    Topics: alpha-Synuclein; Amyloid beta-Peptides; Cell Line, Tumor; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Neuroblastoma; Parkinson Disease; Peptide Fragments; Phosphorylation; tau Proteins; Tauopathies; Ubiquitin-Protein Ligases

2009
Early-onset familial lewy body dementia with extensive tauopathy: a clinical, genetic, and neuropathological study.
    Journal of neuropathology and experimental neurology, 2009, Volume: 68, Issue:1

    We describe a Spanish family in which 3 of 4 siblings had dementia with Lewy bodies, 2 of them starting at age 26 years and the other at 29 years. The father has recently been diagnosed with Lewy body disease, with onset at 77 years. Neuropathological examination of the brain of the index patient disclosed unusual features characterized by diffuse Lewy body disease and generalized neurofibrillary tangle pathology but with no amyloid deposits in any region. Moreover, Lewy body pathology colocalized with neurofibrillary tangles in most affected neurons. Mutation screening that included all coding exons of presenilin 1 (PSEN1), presenilin 2 (PSEN2), alpha-synuclein (SNCA), beta-synuclein (SNCB), microtubule-associated protein tau (MAPT), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA), and exons 16 and 17 of the amyloid precursor protein (APP) genes did not identify any mutation. Genome-wide single nucleotide polymorphism was performed in 4 family members and ruled out any pathogenic duplication or deletion in the entire genome. In summary, we report a unique family with pathologically confirmed early-onset dementia with Lewy bodies with widespread tau and alpha-synuclein deposition. The absence of mutations in genes known to cause Lewy body disease suggests that a novel locus or loci are implicated in this neurodegenerative disease.

    Topics: Adult; Aged, 80 and over; alpha-Synuclein; Brain; DNA Mutational Analysis; DNA-Binding Proteins; Family Health; Female; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Neurofibrillary Tangles; Presenilins; tau Proteins; Tauopathies

2009
The ALS/PDC syndrome of Guam and the cycad hypothesis.
    Neurology, 2009, Feb-03, Volume: 72, Issue:5

    Topics: alpha-Synuclein; Amino Acids, Diamino; Amyotrophic Lateral Sclerosis; Animals; Bacterial Toxins; Causality; Cyanobacteria Toxins; Cycas; Dementia; Disease Models, Animal; Epidemiologic Research Design; Epidemiologic Studies; Flour; Guam; Hazardous Substances; Humans; Incidence; Indonesia; Japan; Marine Toxins; Methylazoxymethanol Acetate; Microcystins; Nerve Degeneration; Parkinsonian Disorders; Plant Extracts; Syndrome; Tauopathies

2009
Absence of alpha-synuclein pathology in postencephalitic parkinsonism.
    Acta neuropathologica, 2009, Volume: 118, Issue:3

    Postencephalitic parkinsonism (PEP), a chronic complication of encephalitis lethargica, is a tauopathy characterized by multisystem neuronal loss and gliosis with widespread neurofibrillary lesions composed of both 3- and 4-repeat (3R and 4R) tau isoforms. Previous immunohistochemical studies in a small number of PEP cases demonstrated absence of Lewy bodies as well as the lack of other alpha-synuclein pathology, classifying PEP as a "pure" tauopathy. Neuropathologic examination of 10 brains with clinico-pathologically verified PEP confirmed widespread neurodegeneration in subcortical and brainstem areas associated with multifocal neurofibrillary pathology comprising both 3R and 4R tau. Very rare beta-amyloid deposits were observed in two elderly patients, while Lewy bodies and neurites or any other alpha-synuclein deposits were completely absent. The causes and molecular background of total absence of alpha-synuclein pathology in PEP, in contrast to most other tauopathies, remain as unknown as the pathogenesis of PEP.

    Topics: Adult; alpha-Synuclein; Amyloid beta-Peptides; Brain; Brain Stem; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nerve Degeneration; Neurons; Parkinson Disease, Postencephalitic; Tauopathies

2009
Leucine-rich repeat kinase 2 colocalizes with alpha-synuclein in Parkinson's disease, but not tau-containing deposits in tauopathies.
    Neuro-degenerative diseases, 2008, Volume: 5, Issue:3-4

    Mutations in leucine-rich repeat kinase 2 (LRRK2) are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson's disease.. To examine whether LRRK2 is directly associated with the pathological structures of Parkinson's disease, dementia with Lewy bodies, and other related disorders using highly specific antibodies to LRRK2.. LRRK2 antibodies strongly labeled brainstem and cortical Lewy bodies, the pathological hallmarks of Parkinson's disease and dementia with Lewy bodies, respectively. We found that 20-100% (mean 60%) of alpha-synuclein-positive Lewy bodies contained LRRK2. While antibodies raised against various regions of LRRK2 were previously shown to label recombinant LRRK2 on Western blots, only antibodies raised against the N- and C-termini, but not the regions containing folded protein domains of LRRK2, immunolabeled Lewy bodies. In Alzheimer's disease, Hirano bodies were found to contain LRRK2 and the neurofibrillary tangles in progressive supranuclear palsy remained unlabeled.. Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of Parkinson's disease and related disorders.

    Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Brain Chemistry; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Middle Aged; Parkinson Disease; Protein Serine-Threonine Kinases; tau Proteins; Tauopathies

2008
Tauopathies and synucleinopathies: do cerebrospinal fluid beta-amyloid peptides reflect disease-specific pathogenesis?
    Journal of neural transmission (Vienna, Austria : 1996), 2007, Volume: 114, Issue:7

    To evaluate variations in amyloid beta (Abeta) peptide pattern in cerebrospinal fluid (CSF) in neurodegenerative disorders. A recently established quantitative urea-based Abeta-sodium-dodecylsulfate-polyacrylamide-gel-electrophoresis with western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide (Abeta1-37, 1-38, 1-39, 1-40, 1-42) pattern in CSF. We asked whether the variation might be useful to further elucidate the overlap between or distinctions among neurodegenerative diseases in Abeta-processing. We used the Abeta-SDS-PAGE/immunoblot to investigate CSF for disease-specific Abeta peptide patterns. CSF samples from 96 patients with mainly clinically diagnosed Alzheimer's disease (n = 15), progressive supranuclear palsy (n = 20), corticobasal degeneration (n = 12), Parkinson's disease (n = 11), multiple systems atrophy (n = 18), and dementia with Lewy-bodies (n = 20) were analysed as well a comparison group (n = 19). The Abeta peptide patterns varied between tauopathies and synucleinopathies and between all diseases and the comparison group, possibly due to the influence of tau and alpha-synuclein on Abeta-processing.

    Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Protein Processing, Post-Translational; tau Proteins; Tauopathies

2007
Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone.
    Journal of neurochemistry, 2007, Volume: 101, Issue:6

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. Previous studies have demonstrated that chronic systemic exposure of Lewis rats to rotenone produced many features of PD, and cerebral tauopathy was also detected in the case of severe weight loss. The present study was designed to assess the neurotoxicity of rotenone after daily oral administration for 28 days at several doses in C57BL/6 mice. In addition, we examined the protective effects of 4-phenylbutyrate (4-PBA) on nigral dopamine (DA) neurons in rotenone-treated mice. 4-PBA was injected intraperitoneally daily 30 min before each oral administration of rotenone. Chronic oral administration of rotenone at high doses induced specific nigrostriatal DA neurodegeneration, motor deficits and the up-regulation of alpha-synuclein in the surviving DA neurons. In contrast to the Lewis rat model, cerebral tauopathy was not detected in this mouse model. 4-PBA inhibited rotenone-induced neuronal death and decreased the protein level of alpha-synuclein. These results suggest that this rotenone mouse model may be useful for understanding the mechanism of DA neurodegeneration in PD, and that 4-PBA has a neuroprotective effect in the treatment of PD.

    Topics: alpha-Synuclein; Animals; Cells, Cultured; Corpus Striatum; Disease Models, Animal; Dopamine; Endoplasmic Reticulum; Humans; Male; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neurons; Oxidative Stress; Parkinsonian Disorders; Phenylbutyrates; Rotenone; Substantia Nigra; Tauopathies

2007
Tau-predominant-associated pathology in a sporadic late-onset Hallervorden-Spatz syndrome.
    Movement disorders : official journal of the Movement Disorder Society, 2006, Volume: 21, Issue:1

    Hallervorden-Spatz syndrome (HSS) is a heterogeneous clinicopathological disorder currently included within the broader title of neurodegeneration with brain iron accumulation (NBIA). The classic histological hallmarks of HSS are axonal spheroids and excessive iron-containing granules accompanied by neuronal loss and gliosis in the globus pallidus and substantia nigra reticulata. In the modern literature, attention has been drawn to the co-occurrence of two other histological markers: Lewy bodies mainly composed of abnormal alpha-synuclein, and neurofibrillary tangles due to hyperphosphorilated tau aggregation. Discrepancies exist regarding the importance of these molecular changes and its relevance for the nosology of HSS. Most authors have emphasized the importance of the Lewy body-like pathology, favoring the inclusion of HSS within the alpha-synucleinopathies. We report on a case of late-onset HSS, with the typical histological findings restricted to the basal ganglia and cerebellum in which tau pathology was exceedingly more abundant than alpha-synuclein pathology. This case contributes to the increasing evidence about the heterogeneity of HSS. We favor the view that the molecular changes and the protein misfolding underlying the Lewy body and tangle formation in HSS/NBIA are secondary to the main pathological process and should not be taken as the basis for its nosological classification.

    Topics: alpha-Synuclein; Axons; Basal Ganglia; Brain; Brain Stem; Diagnosis, Differential; Humans; Inclusion Bodies; Iron; Lewy Bodies; Male; Middle Aged; Myelin Sheath; Neurodegenerative Diseases; Neurofibrillary Tangles; Pantothenate Kinase-Associated Neurodegeneration; Protein Folding; Spheroids, Cellular; tau Proteins; Tauopathies; Thalamic Nuclei

2006
Human brain tissue microarrays as a platform to investigate diseases of the nervous system.
    Brain research, 2006, May-17, Volume: 1089, Issue:1

    We constructed tissue microarray (TMA) blocks containing post-mortem human brain tissue from subjects with clinically and neuropathologically verified Alzheimer's disease (AD), corticobasal degeneration (CBD), progressive supranuclear palsy, Lewy body disease, multisystem atrophy (MSA) as well as an age matched control. Fifteen donor blocks were merged into two TMA blocks containing 72, 2-mm punch core samples with representative brain regions generally affected in degenerative disorders. Hyperphosphorylated-gamma, alpha-synuclein and beta-amyloid-related pathologies were estimated. The diseases were easily recognized by evaluating the two TMA sections and the results assessing TMA sections were comparable with the assessment of the whole brain sections. The assessment of TMA sections revealed concomitant multifocal alpha-synuclein pathology in AD, mild tau-involvement in the case of MSA and a slight AD-type pathology in the case of CBD. These findings emphasize the importance of searching for a variety of pathologies in "the whole brain" rather than restricting the examination to a few vulnerable regions. Furthermore, the TMA methodology clearly reduced the number of sections needed for evaluating the whole brain, it increased the amount of research material generated and furthermore no detailed neuroanatomical knowledge was required for assessment of data.

    Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Biopsy; Brain; Dissection; Female; Humans; Immunohistochemistry; Male; Microarray Analysis; Microtomy; Middle Aged; Neurodegenerative Diseases; Pathology; Plaque, Amyloid; Reproducibility of Results; Sample Size; tau Proteins; Tauopathies

2006
Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat.
    Neurobiology of disease, 2005, Volume: 20, Issue:1

    Using a viral vector for mutant (P301L) tau, we studied the effects of gene transfer to the rat substantia nigra in terms of structural and functional properties of dopaminergic neurons. The mutant tau vector caused progressive loss of pars compacta dopaminergic neurons over time, reduced striatal dopamine content, and amphetamine-stimulated rotational behavior consistent with a specific lesion effect. In addition, structural studies demonstrated neurofibrillary tangles and neuritic pathology. Wild-type tau had similar effects on neuronal loss and rotational behavior. In contrast, mutant alpha-synuclein vectors did not induce rotational behavior, although alpha-synuclein filaments formed in nigrostriatal axons. Dopamine neuron function is affected by tau gene transfer and appears to be more susceptible to tau- rather than alpha-synuclein-related damage in this model. Both tau and alpha-synuclein are important for substantia nigra neurodegeneration models in rats, further indicating their potential as therapeutic targets for human diseases involving loss of dopamine neurons.

    Topics: alpha-Synuclein; Animals; Behavior, Animal; Disease Models, Animal; Dopamine; Gene Transfer Techniques; Genetic Vectors; Male; Motor Activity; Movement Disorders; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Rats; Rats, Sprague-Dawley; Rotation; Substantia Nigra; tau Proteins; Tauopathies

2005
The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy.
    Journal of neurochemistry, 2005, Volume: 95, Issue:4

    Reduced activity of the mitochondrial respiratory chain--particularly complex I--may be implicated in the etiology of both Parkinson's disease and progressive supranuclear palsy, although these neurodegenerative diseases differ substantially as to their distinctive pattern of neuronal cell loss and the predominance of cerebral alpha-synuclein or tau protein pathology. To determine experimentally whether chronic generalized complex I inhibition has an effect on the distribution of alpha-synuclein or tau, we infused rats systemically with the plant-derived isoflavonoid rotenone. Rotenone-treated rats with a pronounced metabolic impairment had reduced locomotor activity, dystonic limb posture and postural instability. They lost neurons in the substantia nigra and in the striatum. Spherical deposits of alpha-synuclein were observed in a few cells, but cells with abnormal cytoplasmic accumulations of tau immunoreactivity were significantly more numerous in the striatum of severely lesioned rats. Abnormally high levels of tau immunoreactivity were found in the cytoplasm of neurons, oligodendrocytes and astrocytes. Ultrastructurally, tau-immunoreactive material consisted of straight 15-nm filaments decorated by antibodies against phosphorylated tau. Many tau+ cell bodies also stained positive for thioflavin S, nitrotyrosine and ubiquitin. Some cells with abnormal tau immunoreactivity contained activated caspase 3. Our data suggest that chronic respiratory chain dysfunction might trigger a form of neurodegeneration in which accumulation of hyperphosphorylated tau protein predominates over deposits of alpha-synuclein.

    Topics: alpha-Synuclein; Amyloid beta-Peptides; Analysis of Variance; Animals; Antineoplastic Combined Chemotherapy Protocols; Behavior, Animal; Benzothiazoles; Body Weight; Caspase 3; Caspases; Cell Death; Cerebral Cortex; Cytarabine; Diagnostic Imaging; Dopamine and cAMP-Regulated Phosphoprotein 32; Doxorubicin; Dystonia; Electron Transport Complex III; Enzyme Activation; Glial Fibrillary Acidic Protein; Immunohistochemistry; Locomotion; Male; Microscopy, Electron, Transmission; Mitochondria; Neurons; Phosphopyruvate Hydratase; Phosphorylation; Posture; Psychomotor Performance; Rats; Rats, Inbred Lew; Rotenone; tau Proteins; Tauopathies; Thiazoles; Time Factors; Tyrosine; Tyrosine 3-Monooxygenase; Ubiquitin; Uncoupling Agents

2005
Pathological properties of the Parkinson's disease-associated protein DJ-1 in alpha-synucleinopathies and tauopathies: relevance for multiple system atrophy and Pick's disease.
    Acta neuropathologica, 2004, Volume: 107, Issue:6

    Mutations in the PARK7 gene DJ-1 are associated with recessive hereditary Parkinson's disease (PD). Fibrillar inclusions of alpha-synuclein comprise the neuropathological hallmarks of PD and related Lewy body diseases as well as multiple system atrophy (MSA). Moreover, neuronal and glial inclusions containing tau have been observed in alpha-synucleinopathy patients. Using a collection of antibodies against DJ-1, we have performed a comprehensive investigation of DJ-1 in alpha-synucleinopathies and tauopathies. DJ-1 was abundantly expressed in reactive astrocytes of patients with neurodegenerative diseases. Likewise, DJ-1 antiserum immunostained reactive astrocytes that became abundant with disease progression in the brain stem of transgenic mice expressing mutant [A30P]alpha-synuclein. Human Lewy bodies as well as Lewy body-like inclusions in the alpha-synuclein transgenic mice were DJ-1 negative. Neuronal tau inclusions were DJ-1 immunopositive in Pick's disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease. In addition, we found DJ-1-immunopositive glial inclusions in CBD, PSP and MSA. Biochemical extraction experiments revealed the specific presence of insoluble, modified DJ-1 in PiD and MSA. Our results suggest that DJ-1 is up-regulated in reactive astrocytes as well as in neuronal and glial cells with specific alpha-synucleinopathy and tauopathy.

    Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Blotting, Western; Epitope Mapping; Female; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Transgenic; Middle Aged; Multiple System Atrophy; Nerve Tissue Proteins; Oncogene Proteins; Pick Disease of the Brain; Protein Deglycase DJ-1; Synucleins; tau Proteins; Tauopathies

2004
Lewy bodies in the amygdala: increase of alpha-synuclein aggregates in neurodegenerative diseases with tau-based inclusions.
    Archives of neurology, 2004, Volume: 61, Issue:12

    Increased attention has been given to alpha-synuclein aggregation in nonsynucleinopathies because alpha-synuclein-containing Lewy bodies (LBs) influence symptoms. However, the spectrum of disorders in which secondary inclusions are likely to occur has not been defined. Amygdala neurons commonly develop large numbers of secondary LBs, making it a practical region for studying this phenomenon.. To characterize the spectrum of diseases associated with LB formation in the amygdala of neurodegenerative disease and control cases.. An autopsy series of 101 neurodegenerative disease and 34 aged control cases. Using immunohistochemistry studies, we examined the amygdala for alpha-synuclein aggregates.. Lewy bodies were often abundant in classic Pick disease, argyrophilic grain disease, Alzheimer disease, and dementia with LBs but not in cases with amygdala degeneration lacking tau-based inclusions, control cases, preclinical disease carriers, or degenerative diseases lacking pathologic involvement of the amygdala. The exposed alpha-synuclein epitopes were similar in all cases containing LBs.. Abnormal alpha-synuclein aggregation in the amygdala is disease selective, but not restricted to disorders of alpha-synuclein and beta-amyloid. Our data are compatible with the notion that tau aggregates predispose neurons to develop secondary LBs.

    Topics: alpha-Synuclein; Amygdala; Humans; Lewy Bodies; Nerve Tissue Proteins; Neurodegenerative Diseases; Synucleins; tau Proteins; Tauopathies

2004
Initiation and synergistic fibrillization of tau and alpha-synuclein.
    Science (New York, N.Y.), 2003, Apr-25, Volume: 300, Issue:5619

    Alpha-synuclein (alpha-syn) and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions characteristic of neurodegenerative diseases. We demonstrate that alpha-syn induces fibrillization of tau and that coincubation of tau and alpha-syn synergistically promotes fibrillization of both proteins. The in vivo relevance of these findings is grounded in the co-occurrence of alpha-syn and tau filamentous amyloid inclusions in humans, in single transgenic mice that express A53T human alpha-syn in neurons, and in oligodendrocytes of bigenic mice that express wild-type human alpha-syn plus P301L mutant tau. This suggests that interactions between alpha-syn and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases.

    Topics: alpha-Synuclein; Amyloid; Animals; Biopolymers; Brain Chemistry; Humans; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Microscopy, Fluorescence; Microscopy, Immunoelectron; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Oligodendroglia; Protein Conformation; Protein Isoforms; Synucleins; tau Proteins; Tauopathies

2003
Genetic loci contributing to age-related hippocampal lesions in mice.
    Neurobiology of disease, 2003, Volume: 13, Issue:2

    C57BL/6J mice develop genetically determined age-related hippocampal granular deposits that have some similarities to lesions seen in the brains of human patients with tau protein related neurodegenerative disorders ("tauopathies"). We sought to identify the genetic loci responsible for these in an F2 intercross of inbred mouse strains C57BL/6J and DBA/2J, using quantitative trait locus (QTL) analysis. Hippocampal lesions were shown to be PAS positive, H and E negative, and immunoreactive for tau protein and alpha synuclein, but not to Abeta 1-40 or Abeta 1-42, or for ubiquitin. These were quantitated by histomorphometry, and QTL analysis revealed a locus on chromosome 7 with a lod score of 6.5 as well as two suggestive loci on chromosome 10. The genomic data indicate that the genetic basis is complex, but with one locus playing a major role in lesion formation. These lesions may represent a useful model for investigating dysregulation of tau protein in the hippocampus.

    Topics: Aging; Alleles; alpha-Synuclein; Aminosalicylic Acid; Amyloid beta-Peptides; Animals; Chromosomes; Female; Genetic Linkage; Hippocampus; Immunohistochemistry; Lod Score; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Nerve Tissue Proteins; Peptide Fragments; Quantitative Trait Loci; Synucleins; tau Proteins; Tauopathies

2003