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Τρίτη 29 Αυγούστου 2017

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Jui-Heng Tseng, Ling Xie, Sheng Song, Youmei Xie, Lauren Allen, Deepa Ajit, Jau-Shyong Hong, Xian Chen, Rick B. Meeker, Todd J. Cohen
The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.

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Teaser

Tau mislocalization and aggregation are implicated in the pathogenesis of Alzheimer's disease. Tseng et al. report that endogenous neuronal tau re-localizes to distinct neuritic foci, which are active sites of calcium deregulation, leading to aberrant tau accumulation. These findings provide insights into the early-stage tau dysfunction that occurs in vulnerable neurons.


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