alpha-synuclein and Pick-Disease-of-the-Brain

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

Our understanding of the structural substrates underlying the dementia syndrome has been transformed by the introduction of the Gallyas silver stain and the application of immunostains for tau, ubiquitin, and alpha-synuclein. Visualization of sequential changes in Alzheimer's disease and the recognition of a new substrate for dementia and dementia with argyrophilic grains, are two of the advances related to the application of the Gallyas method. The specificity of alpha-synuclein for recognizing Lewy bodies enables the unequivocal diagnosis of dementia with Lewy bodies. The diverse entities that constitute the Pick complex can be identified by applying immunostains for tau and ubiquitin in addition to the Gallyas silver stain.

Topics: alpha-Synuclein; Alzheimer Disease; Coloring Agents; Dementia; Diagnosis, Differential; Humans; Lewy Bodies; Nerve Tissue Proteins; Pick Disease of the Brain; Synucleins; tau Proteins; Ubiquitins

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-β, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-β (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-β burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcort

Topics: alpha-Synuclein; Amyloid beta-Peptides; Brain; DNA-Binding Proteins; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Hallucinations; Humans; Pick Disease of the Brain; tau Proteins

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-β and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain Cortical Thickness; CA1 Region, Hippocampal; Case-Control Studies; DNA-Binding Proteins; Entorhinal Cortex; Female; Frontotemporal Lobar Degeneration; Hippocampus; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Neurodegenerative Diseases; Neurofibrillary Tangles; Parahippocampal Gyrus; Pick Disease of the Brain; Plaque, Amyloid; Supranuclear Palsy, Progressive; tau Proteins; Temporal Lobe

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

Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c.1008G>C, p.Q336H) in 1 patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared with sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism, and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p.Q336H mutation formed filaments faster than wild-type tau, especially with 3R tau. It also promoted more microtubule assembly than wild-type tau. We conclude that mutations in MAPT, including p.Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p.Q336H, and another previously reported variant at the same codon (p.Q336R), seems to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau-dependent manner.

Topics: alpha-Synuclein; Brain; DNA Mutational Analysis; Exons; Glutamic Acid; Histidine; Humans; Male; Middle Aged; Mutation; Pick Disease of the Brain; tau Proteins; Ubiquitin

The increasing life expectancy will cause an increasing share for neurodegenerative and dementing illnesses in the total cost for health care. New developments such as the discovery of TDP-43 as disease protein have opened new viewpoints on frontotemporal dementias, as well as its relation to amyotrophic lateral sclerosis. As pathologists and neuropathologists we are committed to contributing to the progress of clinical diagnosis, which often proves difficult, by standardized post-mortem diagnosis. The diagnostic responsibility will increase with the development of new specific therapeutics and knowledge of contraindications such as the use of neuroleptics in patients suffering from Lewy body dementia. The Reference Center for Neurodegenerative Diseases of the German Society of Neuropathology and Neuroanatomy and the German Brain Bank (Brain-Net) at the Institute for Neuropathology, Ludwig-Maximilians-University Munich, are available for diagnosis in difficult or complex cases.

Topics: alpha-Synuclein; Alzheimer Disease; Autopsy; Brain; Diagnosis, Differential; DNA-Binding Proteins; Humans; Lewy Body Disease; Mutation; Nerve Tissue Proteins; Neurodegenerative Diseases; Pick Disease of the Brain; tau Proteins

Mutations in the progranulin (GRN) gene have recently been reported as a cause of the frontotemporal dementia (FTD) syndrome. We performed a clinical, neuropathological and molecular genetic study of two families with FTD and the same novel mutation in GRN. Age of onset ranged from 35 to 75 years and all individuals progressed to a severe dementia syndrome with a mean disease duration of approximately 6-10 years. Variable clinical presentations included language impairment, behaviour change or parkinsonism. Seven total autopsies in the families (five in Family 1, two in Family 2) showed gross and microscopic evidence of neuronal loss in the neocortex, striatum, hippocampus and substantia nigra. All cases with material available for immunohistochemistry had cytoplasmic and intranuclear ubiquitin positive, tau negative inclusions that stained best with an antibody to the TDP43 protein. In addition, all but one had evidence of distinctive tau pathology. Two cases in Family 1 also had alpha-synuclein (SNCA) pathology, one with diffuse neocortical inclusions and neurites and unusual striatal cytoplasmic inclusions. Affected persons in both families had the same mutation in GRN (c.709-2A>G). A minigene construct showed that this mutation alters splicing of exon 7 and results in reduced mRNA message in brain. A single GRN mutation in these two families was associated with variable clinical presentations consistent with the FTD syndrome. All cases had ubiquitin/TDP43 immuno-positive inclusions and most had additional tau pathology. Two cases had SNCA pathology. These findings suggest a link between mutations in GRN and aggregation of tau, TDP43 and SNCA.

Topics: Adult; Age of Onset; Aged; alpha-Synuclein; Blotting, Western; Brain; Case-Control Studies; Corpus Striatum; DNA-Binding Proteins; Female; Genotype; Hippocampus; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Neocortex; Pedigree; Pick Disease of the Brain; Progranulins; Sequence Analysis, DNA; Substantia Nigra; tau Proteins; Ubiquitin

Impaired transduction of transforming growth factor-beta signaling has recently been implicated in Alzheimer disease. Transforming growth factor-beta signals are transduced by Smads, which are phosphorylated and translocated to the nucleus, where they initiate gene transcription. In Alzheimer disease, neurofibrillary tangles sequester phosphorylated Smad 2/3 (pSmad2/3) and reduce its nuclear translocation. We have now investigated the relationship between pSmad2/3 and phospho-tau in 3 other tauopathies, Pick disease, progressive supranuclear palsy, and corticobasal degeneration, and in 2 alpha-synucleinopathies, dementia with Lewy bodies and multiple system atrophy. In Pick disease, progressive supranuclear palsy, and corticobasal degeneration, pSmad2/3 was demonstrated in neuronal and glial nuclei but also colocalized with cytoplasmic tau inclusions. No pSmad2/3 was detected in glial cytoplasmic inclusions in multiple system atrophy or in Lewy bodies in dementia with Lewy bodies. Our data indicate that phospho-tau but not alpha-synuclein cytoplasmic inclusions bind pSmad2/3. The preservation of neuronal nuclear pSmad2/3 in Pick disease, progressive supranuclear palsy, and corticobasal degeneration suggests that cytoplasmic sequestration of pSmad2/3 is likely to have less impact on transforming growth factor-beta signal transduction in these diseases than in Alzheimer disease.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Blotting, Western; Brain; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Body Disease; Male; Multiple System Atrophy; Neurodegenerative Diseases; Phosphorylation; Pick Disease of the Brain; Protein Transport; Smad Proteins; Supranuclear Palsy, Progressive; tau Proteins

Abnormal solubility and aggregation of alpha-synuclein have been observed in the frontal cortex in three cases with Pick's disease (PiD) when compared with age-matched controls. Bands of 45 kDa and higher molecular weight were detected in the SDS-soluble fractions only in PiD. Patterns in PiD differed from that observed in the cerebral cortex in Lewy body diseases which were examined in parallel. Immunoblots to alpha-synuclein nitrated in tyrosines revealed bands of 45 and 60 kDa in Dxc- and SDS-soluble fractions in the frontal cortex (which is vulnerable to PiD) but not in the occipital cortex (which is resistant to this degenerative disease). Moreover, nitrated alpha-synuclein was found in Lewy bodies and neurites in synucleinopathies but diffusely in the cytoplasm of scattered neurons in PiD. These findings demonstrate abnormal and distinct alpha-synuclein solubility and aggregation, and alpha-synuclein nitration without formation of Lewy bodies in the frontal cortex in PiD.

Topics: Aged; alpha-Synuclein; Blotting, Western; Case-Control Studies; Female; Frontal Lobe; Humans; Immunohistochemistry; Male; Molecular Weight; Parkinson Disease; Pick Disease of the Brain; Postmortem Changes; Tyrosine

G-protein coupled receptor kinases (GRKs) constitute a serine/threonine kinase family playing a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors. Recently, GRK2 and GRK5 have been demonstrated to phosphorylate alpha-synuclein (Ser129) and other synuclein isoforms. We studied colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies. We found that Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease (LBD) and LBD mixed with Alzheimer disease (AD + LBD). Instead, GRK2 but not GRK5 colocalized with 40% to 50% of neurofibrillary tangles in AD + LBD and AD brains. In disorders with less prominent alpha-synucleinopathy, neuronal and glial fibrillary tau deposits known to contain distinct subsets of tau isoforms were also positive for GRK2. These deposits included tufted astrocytes and coiled bodies in progressive supranuclear palsy, astrocytic plaques in corticobasal degeneration, and Pick bodies in Pick disease. In addition, paired helical filaments isolated from AD and AD + LBD brains were found to immunogold-label for GRK2, suggesting that GRK2 could be a potential tau kinase associated with fibrillary tau. Our studies indicate that GRK2 is a novel component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding. GRK2 may play a role in hyperphosphorylation of tau in tauopathies.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; beta-Adrenergic Receptor Kinases; Brain; Female; G-Protein-Coupled Receptor Kinase 2; G-Protein-Coupled Receptor Kinase 5; Humans; Lewy Bodies; Lewy Body Disease; Male; Neurodegenerative Diseases; Neurofibrillary Tangles; Neuroglia; Neurons; Phosphorylation; Pick Disease of the Brain; Protein Serine-Threonine Kinases; Supranuclear Palsy, Progressive; tau Proteins

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

Clusterin/apolipoprotein J protein expression in cases with "alpha-synucleinopathies", such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), was investigated using an immunohistochemical method for the labeling of multiple antigens. About 50% of the cortical Lewy bodies in the cases with DLB were immunoreactive for clusterin, whereas brain-stem Lewy bodies in PD and DLB were rarely associated with clusterin. Clusterin was also immunopositive in around 10% of the glial cytoplasmic inclusions (GCIs) in the cases with MSA. Colocalization of clusterin with alpha-synuclein in such bodies or inclusions was clearly correlated with the immunostaining pattern of alpha-synuclein. Subcellular localization of clusterin was almost completely overlapped with the homogeneous immunoreaction of alpha-synuclein in the cortical Lewy bodies; however, clusterin immunoreactivity was not detected in the halo or ring-like structures of the brain-stem Lewy bodies. Furthermore, some Lewy bodies with intense immunoreactivity for clusterin showed only a weak signal for alpha-synuclein. These results suggest that clusterin may modify the formation of alpha-synuclein-positive inclusion bodies such as Lewy bodies and GCIs, through a previously proposed chaperone property of clusterin.

Topics: alpha-Synuclein; Alzheimer Disease; Apolipoproteins E; Brain; Clusterin; Glycoproteins; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Bodies; Lewy Body Disease; Molecular Chaperones; Multiple System Atrophy; Nerve Tissue Proteins; Neurofibrillary Tangles; Neuroglia; Parkinson Disease; Peptide Fragments; Pick Disease of the Brain; Supranuclear Palsy, Progressive; Synucleins

Recent studies have shown that neurofibrillary tangles frequently coexist with alpha-synuclein (alpha-S)-positive fibrillary inclusions in the limbic system in Alzheimer's disease. To elucidate whether alpha-, beta- and gamma-S immunoreactivity is present in Pick bodies (PBs), we examined immunohistochemically and immunoelectron microscopically the brains from three patients with Pick's disease. Numerous PBs were distributed widely, and were occasionally immunoreactive for alpha-S and beta-S, but not for gamma-S in all three cases. However, these immunoreactive PBs were almost all restricted to the dentate gyrus. Despite the co-localization of phosphorylated tau and alpha-S or beta-S (as evidenced by double-labeling immunohistochemistry), immunoelectron microscopy revealed that alpha-S and beta-S immunoreactivity occurs in granular and vesicular structures, but not in filamentous structures. These findings suggest that alpha-S and beta-S are up-regulated in the neuronal perikarya but they are not incorporated into the constituent filaments of PBs, and that the preferential distribution of alpha-S- and beta-S-positive PBs in the dentate gyrus may represent the cellular response to PB formation in this particular system.

Topics: Aged; alpha-Synuclein; beta-Synuclein; Dentate Gyrus; Humans; Immunohistochemistry; Microscopy, Immunoelectron; Middle Aged; Nerve Tissue Proteins; Phosphorylation; Pick Disease of the Brain; Synucleins; tau Proteins