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Cell Rep. 2017 Aug 29;20(9):2169-2183. doi: 10.1016/j.celrep.2017.07.082.

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology.

Author information

1
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
2
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
3
Neuropharmacology Section, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
4
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA.
5
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: toddcohen@neurology.unc.edu.

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.

KEYWORDS:

Alzheimer’s disease; deacetylase; excitotoxic; neuroinflammatory; tau

PMID:
28854366
PMCID:
PMC5578720
DOI:
10.1016/j.celrep.2017.07.082
[Indexed for MEDLINE]
Free PMC Article

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