Rates of brain acetylome remodeling in a mouse model of diabetes and tauopathy

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Alzheimer's disease (AD) is one of the top ten causes of death in the United States, and there is no cure. AD is characterized by tauopathy, the accumulation of hyperphosphorylated microtubule- associated protein tau (MAPT, tau), and is linked to metabolic dysregulation. Type 2 diabetes mellitus (T2DM) is a risk factor for late-onset AD, but the mechanistic link between the two is unclear. Post-translational protein lysine N(epsilon) acetylation by the central metabolite acetyl-CoA has been identified as an essential regulatory mechanism in intermediary metabolism, epigenetics, and protein stability. T2DM is characterized by altered substrate metabolism, which impacts acetylation and deacetylation co-factors NAD+ and acetyl-CoA. Dysregulated histone and tau acetylation have been linked with age-dependent memory impairment. In vitro studies suggest that acetylation contributes to tau aggregation. The in vivo impact of site-specific acetylation on brain protein, including tau turnover, is unknown. To investigate this, we developed a 2H2O (stable isotope)-based mass spectrometry method to quantify protein turnover and assess the effect of post-translational modifications (PTMs) on protein stability in vivo. The study aims to evaluate the role of acetylation on brain proteome dynamics in the htau mouse model of AD. The first aim quantifies proteome and acetylome dynamics in the hippocampus and frontal cortex of diet-induced diabetic and non-diabetic AD mice to determine the effect of T2DM-related dysregulated acetylation on brain protein stability in vivo. The second aim assesses the role of T2DM on the acetylation turnover of brain proteins in vivo. The research team will also determine how T2DM-related altered acetylation contributes to tauopathy and cognitive decline in AD. These experiments will establish the feasibility of the acetylome dynamics method and motivate the development of new AD therapies.