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Role of acetylation in a tauopathy mouse model of Alzheimer's disease (AD)

Alzheimer’s disease (AD) is one of the top ten causes of death in the United ÐÓ°ÉÊÓƵs, but it still has no cure. In addition to the aggregation of amyloid β (Aβ), AD is characterized by tauopathy, the accumulation of hyperphosphorylated microtubule-associated protein tau (MAPT, tau). Tauopathy is also associated with impaired protein synthesis and accumulation of acetylated tau. Emerging evidence suggests that metabolic dysregulation is involved in these changes.

Post-translational protein lysine N (epsilon) acetylation by the central metabolite acetyl-CoA has emerged as an essential regulatory mechanism in intermediary metabolism, epigenetics, and protein stability. AD is associated with altered brain metabolism and proteostasis, i.e., protein synthesis, degradation, and post-translational modifications (PTMs). Increased acetylated tau (ac-tau) is also reported in tauopathy and altered histone acetylation has been linked with age-dependent memory impairment in mice. In vitro studies show that acetylation of tau increases its stability. The in vivo impact of site-specific acetylation on brain protein turnover is unknown. The lack of nonradioactive methods has hindered the quantitative turnover assessment of individual proteins. We developed a stable isotope-based mass spectrometry method, which allows us to quantify protein turnover and assess the effect of post-translational modifications (PTMs) on protein stability in vivo. Here, we will use this method to evaluate the role of acetylation on brain proteome dynamics in the htau mouse (Jax#05491) model of AD that over-expresses all six human tau isoforms. We will perform unbiased proteomics and acetylomics analysis in the htau mouse brain to assess the role of acetylation in tauopathy.