Format

Send to

Choose Destination
Nat Med. 2015 Oct;21(10):1154-62. doi: 10.1038/nm.3951. Epub 2015 Sep 21.

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

Author information

1
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
2
Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
3
Gladstone Institute of Virology and Immunology, San Francisco, California, USA.
4
Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA.
5
Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, California, USA.
6
Neuroscience Graduate Program, University of California, San Francisco, San Francisco, California, USA.
7
Buck Institute for Research on Aging, Novato, California, USA.
8
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
9
Department of Neuroscience, University of California, San Diego, San Diego, California, USA.

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.

PMID:
26390242
PMCID:
PMC4598295
DOI:
10.1038/nm.3951
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center