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Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.

TitleCritical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.
Publication TypeJournal Article
Year of Publication2015
AuthorsMin S-W, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, S Minami S, Defensor E, Mok SAnn, Sohn PDongmin, Schilling B, Cong X, Ellerby L, Gibson BW, Johnson J, Krogan N, Shamloo M, Gestwicki J, Masliah E, Verdin E, Gan L
JournalNat Med
Volume21
Issue10
Pagination1154-62
Date Published2015 Oct
ISSN1546-170X
KeywordsAcetylation, Animals, Behavior, Animal, Cognition Disorders, Humans, Mice, Neurodegenerative Diseases, tau Proteins
Abstract

Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.

DOI10.1038/nm.3951
Alternate JournalNat. Med.
PubMed ID26390242
PubMed Central IDPMC4598295
Grant List1R01AG036884 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
RL1 NS062413 / NS / NINDS NIH HHS / United States
R01 NS059690 / NS / NINDS NIH HHS / United States
NS40251 / NS / NINDS NIH HHS / United States
R24 DK085610 / DK / NIDDK NIH HHS / United States
R01AG030207 / AG / NIA NIH HHS / United States
P30 NS065780 / NS / NINDS NIH HHS / United States
P30NS065780 / NS / NINDS NIH HHS / United States
R01 AG030207 / AG / NIA NIH HHS / United States
NS062413 / NS / NINDS NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
P30 MH062512 / MH / NIMH NIH HHS / United States
R01 NS040251 / NS / NINDS NIH HHS / United States
S10 RR024615 / RR / NCRR NIH HHS / United States