Acetylation changes in alcoholic Alzheimer's disease mouse brains

Summary Alzheimer’s disease (AD), the most common form of dementia, is a growing concern for the aging population, and alcohol intake accelerates brain aging and AD risk. Alcohol may worsen AD by inhibiting brain glucose metabolism to acetyl-CoA, essential for energy and protein acetylation, and by depleting NAD+, which is crucial for deacetylation. AD involves acetylation changes in histones and tau, marked by phosphorylated tau (pTau) buildup. Alcohol exposure alters brain histone acetylation and increases pTau in rodents, but the role of alcohol in amyloid β (Aβ)- independent, tau-based dementia remains unclear. We will use the htau mouse model, an Aβ-independent model of tauopathy, and stable isotope- based flux studies, along with pharmacological and molecular techniques, to investigate alcohol- induced disruptions in brain histone and tau acetylation and their role in tauopathy and cognitive decline. We will measure acetylation dynamics and acetylation-dependent protein turnover to assess whether these disruptions promote the shift from normal to pathological aging. We hypothesize that alcohol accelerates tauopathy through histone acetylation–linked transcriptional changes and impaired tau degradation. Six-month-old htau mouse will have intermittent access to alcohol or water for four months to study neural and behavioral pathology. In Aim 1, we will use isotope techniques and modulators of histone acetylation and autophagy to investigate whether (i) alcohol-disrupted histone acetylation results from impaired brain glucose metabolism using 13C- glucose and ethanol tracing, (ii) reduced H4K16ac contributes to autophagy inhibition related to tauopathy, and whether an HDAC inhibitor can prevent this, and (iii) changes in H4K16Ac transcriptionally regulate autophagy (ChIP assay). In Aim 2, we will investigate whether alcohol-induced NAD+ depletion contributes to increased tau acetylation and tauopathy by modulating tau deacetylation through NAD+ precursor supplementation while also characterizing NAD+ metabolism, acetylation-dependent tau aggregation and their relationship to tauopathy and cognition. If successful, this proposal will assess the mechanisms by which alcohol intake synergizes with aging to accelerate tau-based AD. Project Number: 1R21AG091377-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Takhar Kasumov | Institution: NORTHEAST OHIO MEDICAL UNIVERSITY, ROOTSTOWN, OH | Award Amount: $439,865 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 AN-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11230978