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.
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We thank V. Haroutunian (The Icahn School of Medicine at Mount Sinai) and W.W. Seeley (UCSF) for human brain samples; B. Hann and J. Freimuth (UCSF) for oral gavage; L. Petrucelli (Mayo Clinic) for ac-KIGS antibody; P. Davies (Feinstein Institute for Medical Research) for MC1 and PHF-1 antibodies, Prothena Biosciences for 12E8 antibody; R. Ponnusamy and N. Devidze for advice on behavioral analyses; D. Song for PK analysis (PPL Inc); M. Finucane and S. Liu for advice on statistical analysis; L. Mucke and S. Meada for insightful discussions; L. Grinberg for technical advice on pathological analysis; C. Brennecka, G. Howard and S. Ordway for editorial review; J. Carroll and G. Maki for graphics assistance; E. Nguyen for administrative assistance and AB SCIEX for evaluation of the TripleTOF 5600 at the Buck Institute. This work was supported by a grant from the Tau Consortium (to L.G.) and US National Institutes of Health (NIH) grants 1R01AG036884 and R01AG030207 (to L.G.). We acknowledge the support of the NIH to L.E. (NIH NS40251 and NIH NS062413), and instrumentation from the NCRR shared instrumentation grant S10 RR024615 (to B.W.G.). Behavioral data were obtained with the help of the Gladstone Institutes' Neurobehavioral Core (supported by NIH grant P30NS065780).
The authors declare no competing financial interests.
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Min, SW., Chen, X., Tracy, T. et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21, 1154–1162 (2015). https://doi.org/10.1038/nm.3951
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