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Critical Molecular and Cellular Contributors to Tau Pathology.

ABSTRACT: Tauopathies represent a group of neurodegenerative diseases including Alzheimer's disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic 'tau seeds' from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cells or adjacent glial cells via receptor-mediated endocytosis facilitate disease spread through the brain. While neuroprotective effects of glial cells-including phagocytotic microglial and astroglial phenotypes-have been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (MAPT) gene mutations and the strongest genetic risk factor of tauopathies-an increase in the presence of the ?2 allele of apolipoprotein E (ApoE)-provide important clues to understanding tau pathology progression. In this review, we describe the crucial signaling pathways and diverse cellular contributors to the progression of tauopathies. A systematic understanding of disease pathogenesis provides novel insights into therapeutic targets within altered signaling pathways and is of great significance for discovering effective treatments for tauopathies.

SUBMITTER: Song L

PROVIDER: S-EPMC7918468 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Critical Molecular and Cellular Contributors to Tau Pathology.

Song Liqing L Wells Evan A EA Robinson Anne Skaja AS

Biomedicines 20210214 2

Tauopathies represent a group of neurodegenerative diseases including Alzheimer's disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic 'tau seeds' from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cel ...[more]

PMID: 33672982

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Project description:BackgroundMolecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer's disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer's disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly.MethodsTo determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.ResultsCLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.ConclusionsThe findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

Project description:Preclinical Alzheimer's disease describes some individuals who harbour Alzheimer's pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer's-related neurodegeneration. We therefore conducted a genome-wide association study using 5 891 064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies (n = 1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency >0.01), including APOE-ɛ4 and APOE-ɛ2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset (n = 808) where amyloid burden was assessed by Pittsburgh Compound B ([11C]-PiB) positron emission tomography. In this study, we found that APOE-ɛ4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ɛ4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene (P = 1.46 × 10-8; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 × amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (P = 0.0112) where amyloid burden was assessed by positron emission tomography. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis.

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Critical Molecular and Cellular Contributors to Tau Pathology.

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Critical Molecular and Cellular Contributors to Tau Pathology.

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