Sang-Won Min1,2,10, Xu Chen1,2,10, Tara E Tracy1,2, Yaqiao Li1, Yungui Zhou1, Chao Wang1,2, Kotaro Shirakawa3, S Sakura Minami1,2, Erwin Defensor4, Sue Ann Mok5, Peter Dongmin Sohn1,6, Birgit Schilling7, Xin Cong7, Lisa Ellerby7, Bradford W Gibson7, Jeffrey Johnson8, Nevan Krogan8, Mehrdad Shamloo4, Jason Gestwicki5, Eliezer Masliah9, Eric Verdin3 & Li Gan1,2,6
1Gladstone Institute of Neurological Disease, San Francisco, California, USA. 2Department of Neurology, University of California, San Francisco, San Francisco, California, USA. 3Gladstone Institute of Virology and Immunology, San Francisco, California, USA. 4Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA. 5Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, California, USA. 6Neuroscience Graduate Program, University of California, San Francisco, San Francisco, California, USA. 7Buck Institute for Research on Aging, Novato, California, USA. 8Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA. 9Department of Neuroscience, University of California, San Diego, San Diego, California, USA. 10These authors contributed equally to this work.
Correspondence to : Li Gan or Eric Verdin
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.