The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology.
Publication/Presentation Date
8-29-2017
Abstract
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.
Volume
20
Issue
9
First Page
2169
Last Page
2183
ISSN
2211-1247
Published In/Presented At
Tseng, J. H., Xie, L., Song, S., Xie, Y., Allen, L., Ajit, D., Hong, J. S., Chen, X., Meeker, R. B., & Cohen, T. J. (2017). The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology. Cell reports, 20(9), 2169–2183. https://doi.org/10.1016/j.celrep.2017.07.082
Disciplines
Medicine and Health Sciences
PubMedID
28854366
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article