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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 States, 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.