Chronic alcohol exposure during young adulthood attenuates microglial reactivity and downstream immune response pathways in a mouse model of tauopathy later in life.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the buildup of amyloid-β and tau protein tangles. Alcohol use has been identified as a risk factor for AD; however, the molecular mechanisms underlying this potential causal link remain elusive. An emerging area of research focuses on the role of microglia, the brain's innate immune cells, in AD pathogenesis, with evidence suggesting that alcohol exposure may prime microglia to exhibit an exaggerated immune response when they are subsequently exposed to proinflammatory stimuli.

Methods: We used a single 10-day chronic-plus-binge alcohol exposure model in male and female C57BL/6J mice aged 8-10 weeks One month later, tauopathy was induced via adenoviral vector (AAV)-mediated overexpression of h-p301L Tau. After 2.5 months, the mice underwent behavioral and cognitive testing. Two weeks later, microglia were collected using fluorescence-activated cell sorting (FACS) and processed for unbiased, mass spectrometry-based proteomic analysis to determine the molecular pathways related to microglial reactivity.

Results: Microglia from mice exposed to alcohol in young adulthood exhibited a blunted immune response when challenged with AAV-mediated delivery and accumulation of human tau later in life. This was characterized by decreased expression of MHC II- and interferon-associated proteins and bioinformatic prediction of inhibited inflammation-related pathways in the absence of gross histological, behavioral, or cognitive deficits. These results demonstrate unique, temporally specific microglial reactivity to tau that is modulated by early adulthood alcohol exposure, implicating a microglial response that could negatively affect the mechanisms necessary for tau clearance and potentially exacerbate tau pathogenesis.

Conclusions: This study provides novel insights into the long-term effects of alcohol exposure in early adulthood on microglial function and the complexity of context-dependent microglial involvement in tauopathy. Consideration of early-adulthood environmental factors is critical for understanding and potentially mitigating the risk of neurodegenerative diseases, such as AD.