Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Biochemistry
• Gerontology

Background:

• Alzheimer's disease (AD) is a growing concern for aging populations.
• Alcohol intake is linked to accelerated brain aging and increased AD risk.
• Normal aging and AD involve altered proteostasis and cognitive decline, regulated by acetylation; alcohol's specific impact on acetylation-dependent tauopathy is unknown.

Purpose of the Study:

• To investigate the role of acetylation in age-dependent tauopathy.
• To examine the effects of acute alcohol exposure on tauopathy markers and acetylation.
• To determine alcohol's impact on tau turnover and acetylation pathways.

Main Methods:

• Immunoassays were used to analyze acetylation in htau mice across different disease stages.
• Acute alcohol exposure (time- and dose-dependent) assessed tauopathy markers.
• Mass spectrometry with EtOH-d6 and ²H₂O tracing investigated cortical acetylation and tau turnover.

Main Results:

• In female htau mice, cortical acetylated tau (TauK174ac) increased with age and disease, correlating with total tau.
• Alcohol exposure elevated TauK174ac, TauS202p, and total tau, and increased histone acetylation (H4K16, H3K9).
• Alcohol-derived acetate contributed to histone acetylation; tau acetylation was not directly affected, but tau turnover was reduced, especially for acetylated forms.

Conclusions:

• Alcohol-induced brain acetylation disruptions may accelerate cognitive decline via epigenetic changes and impaired tau turnover.
• Females may be more vulnerable to alcohol-accelerated tauopathy due to higher tau acetylation and potential protein degradation impairment.
• Further research is needed to explore chronic alcohol consumption effects and alcohol's role in tau degradation pathways.