Abstract
A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau.
Highlights
A central question in Alzheimer’s Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology
Because no mutation in the tau gene has been identified in familial AD (fAD) or late-onset AD (LOAD) patients and expression of human wild-type tau failed to elicit tau pathology[41], current mouse models of tau pathology are primarily based on transgenes expressing tau mutants linked to FTDP-17
It is well recognized that endogenous tau can be hyperphosphorylated in mouse models of b-amyloidosis[40], whether the neuritic plaque is necessary and sufficient to facilitate the pathological conversion of wild-type tau is not known
Summary
A central question in Alzheimer’s Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. While previous studies showed that accumulation of Ab could facilitate tau aggregation in FTDP-17 linked mutant Tau mice[9,10,11,12,13], no such evidence have been demonstrated using a non-mutant tau model It is not known whether the neuritic plaque is necessary and sufficient to drive the conversion of wild-type tau. The tau pathology occurring in these FTDP-17-linked tau models is sufficient to drive cell death independent of Ab plaques[44], supporting the view that these mice may be good models of FTDP-17, but not of AD To address this critical unmet need, we developed a mouse model in which wild-type tau is converted into pathological tau aggregates and NFT that are propagated through neuronal circuits to drive neuron loss in a neuritic plaque-dependent manner. Our results offer novel mechanistic insight for the pathogenesis of AD
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