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

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 how it causes neurodegeneration remains unclear. Here we identified tau acetylation at K174 as an early change in AD brains and as a critical determinant in tau homeostasis and toxicity in mice. An acetyl-mimicking mutant (K174Q) slows down tau turnover and induces cognitive deficits in vivo. The acetyltransferase p300-induced tau acetylation is inhibited by a prescription drug salsalate/salicylate, which enhances tau turnover and reduces tau levels. In the PS19 transgenic mouse model of FTD, administering salsalate after disease onset inhibited p300 activity, lowered ac-K174 and total tau levels, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate/salicylate are diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.