amyloid-beta-peptides and Tauopathies

To investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls.. We developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44).. The p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and β-amyloid 40, but not β-amyloid 42.. This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation.. This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aphasia, Primary Progressive; Cohort Studies; Diagnosis, Differential; Female; Frontotemporal Dementia; Humans; Immunoassay; Male; Middle Aged; Neurodegenerative Diseases; Peptide Fragments; Predictive Value of Tests; Reproducibility of Results; Sensitivity and Specificity; Supranuclear Palsy, Progressive; tau Proteins; Tauopathies

Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibodies, Monoclonal; Brain; Cells, Cultured; Drug Implants; Immunization, Passive; Mice; Mice, Transgenic; Neuroprotection; Peptide Fragments; Plaque, Amyloid; Recombinant Proteins; Subcutaneous Absorption; Tauopathies

Alzheimer's disease (AD) is a devastating disorder that is clinically characterized by a comprehensive cognitive decline. Accumulation of the amyloid-beta (Aβ) peptide plays a pivotal role in the pathogenesis of AD. In AD, the conversion of Aβ from a physiological soluble monomeric form into insoluble fibrillar conformation is an important event. The most toxic form of Aβ is oligomers, which is the intermediate step during the conversion of monomeric form to fibrillar form. There are at least two types of oligomers: oligomers that are immunologically related to fibrils and those that are not. In transgenic AD animal models, both active and passive anti-Aβ immunotherapies improve cognitive function and clear the parenchymal accumulation of amyloid plaques in the brain. In this report we studied effect of immunotherapy of two sequence-independent non-fibrillar oligomer specific monoclonal antibodies on the cognitive function, amyloid load and tau pathology in 3xTg-AD mice. Anti-oligomeric monoclonal antibodies significantly reduce the amyloid load and improve the cognition. The clearance of amyloid load was significantly correlated with reduced tau hyperphosphorylation and improvement in cognition. These results demonstrate that systemic immunotherapy using oligomer-specific monoclonal antibodies effectively attenuates behavioral and pathological impairments in 3xTg-AD mice. These findings demonstrate the potential of using oligomer specific monoclonal antibodies as a therapeutic approach to prevent and treat Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibodies, Monoclonal; Avoidance Learning; Cognition; Cognition Disorders; Disease Models, Animal; Female; Gene Knock-In Techniques; Maze Learning; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Peptide Fragments; Presenilin-1; tau Proteins; Tauopathies; Vaccination

Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering beta-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3beta (GSK3beta). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

Topics: Acetylation; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cells, Cultured; Chromatin Immunoprecipitation; Cognition Disorders; Disease Models, Animal; Embryo, Mammalian; Hippocampus; Histones; Humans; Maze Learning; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurons; Peptide Fragments; Phenylbutyrates; Tauopathies

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Genetic Predisposition to Disease; Humans; Mice; Neurofibrillary Tangles; Peptide Fragments; Plaque, Amyloid; tau Proteins; Tauopathies

A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Abeta) and numbers of Abeta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans.

Topics: Alzheimer Disease; Amygdala; Amyloid beta-Peptides; Animals; Avoidance Learning; Behavior, Animal; Cerebral Cortex; Disease Models, Animal; Female; Hippocampus; Male; Maze Learning; Mental Disorders; Mice; Mice, Transgenic; Motor Activity; Paroxetine; Peptide Fragments; Selective Serotonin Reuptake Inhibitors; Swimming; Tauopathies

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