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Tau deletion impairs intracellular ?-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models.

ABSTRACT: BACKGROUND: Tau is an axonal protein that binds to and regulates microtubule function. Hyper-phosphorylation of Tau reduces its binding to microtubules and it is associated with ?-amyloid deposition in Alzheimer's disease. Paradoxically, Tau reduction may prevent ?-amyloid pathology, raising the possibility that Tau mediates intracellular A? clearance. The current studies investigated the role of Tau in autophagic and proteasomal intracellular A?1-42 clearance and the subsequent effect on plaque deposition. RESULTS: Tau deletion impaired A? clearance via autophagy, but not the proteasome, while introduction of wild type human Tau into Tau-/- mice partially restored autophagic clearance of A?1-42, suggesting that exogenous Tau expression can support autophagic A?1-42 clearance. Tau deletion impaired autophagic flux and resulted in A?1-42 accumulation in pre-lysosomal autophagic vacuoles, affecting A?1-42 deposition into the lysosome. This autophagic defect was associated with decreased intracellular A?1-42 and increased plaque load in Tau-/- mice, which displayed less cell death. Nilotinib, an Abl tyrosine kinase inhibitor that promotes autophagic clearance mechanisms, reduced A?1-42 only when exogenous human Tau was expressed in Tau-/- mice. CONCLUSIONS: These studies demonstrate that Tau deletion affects intracellular A?1-42 clearance, leading to extracellular plaque.

SUBMITTER: Lonskaya I

PROVIDER: S-EPMC4247762 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Tau deletion impairs intracellular β-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models.

Lonskaya Irina I Hebron Michaeline M Chen Wenqiang W Schachter Joel J Moussa Charbel C

Molecular neurodegeneration 20141110

<h4>Background</h4>Tau is an axonal protein that binds to and regulates microtubule function. Hyper-phosphorylation of Tau reduces its binding to microtubules and it is associated with β-amyloid deposition in Alzheimer's disease. Paradoxically, Tau reduction may prevent β-amyloid pathology, raising the possibility that Tau mediates intracellular Aβ clearance. The current studies investigated the role of Tau in autophagic and proteasomal intracellular Aβ1-42 clearance and the subsequent effect on ...[more]

PMID: 25384392

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Project description:Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of ?-amyloid (A?). However, the accumulation of A? begins slowly, years before biomarkers become abnormal. We used longitudinal [11C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans (N = 71; mean age 75 years; 35% male). We used [18F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample (N = 37). We found evidence for an inverted-U relationship between baseline A? levels and A? slope in asymptomatic older adults, suggesting a slowing of A? accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of A? predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of A? increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative.SIGNIFICANCE STATEMENT The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.

Dataset Information

Tau deletion impairs intracellular ?-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models.

Publications

Tau deletion impairs intracellular β-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models.

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