Pathology-Specific Modulation of Corticostriatal Circuitry by Chronic Alcohol Consumption in Alzheimers Disease Mouse Models

Abstract

Chronic alcohol use is a major modifiable risk factor for Alzheimers disease (AD), yet the mechanisms by which it modulates AD pathophysiology remain unclear. Here, we examined circuit-level and pathological changes in two distinct AD mouse models, humanized A{beta} knock-in (hAPP-KI) (A{beta}-driven) and PS19 (tau-driven), subjected to a chronic intermittent alcohol exposure paradigm. In hAPP-KI mice, alcohol increased A{beta} accumulation and excitatory transmission in the medial prefrontal cortex (mPFC) while reducing corticostriatal transmission and striatal cholinergic output. These alterations were accompanied by enhanced recruitment of microglia around A{beta} plaques. In contrast, alcohol-exposed PS19 mice displayed elevated mPFC-to-dorsomedial striatum (DMS) glutamatergic transmission and increased tau phosphorylation without significant changes in microglial activation or local mPFC excitatory drive. In wild-type mice, microglial depletion enhanced glutamatergic transmission onto cortical neurons, suggesting a homeostatic role for microglia in maintaining excitatory balance. Together, these findings reveal pathology-specific effects of alcohol on circuit dysfunction and propose microglia as an important modulator of alcohol-induced synaptic remodeling in the early stage of AD. HighlightsO_LIChronic alcohol exposure modulates glutamatergic transmission and neuroimmune responses in pathology-specific manners across A{beta}- and tau-driven Alzheimers disease mouse models. C_LIO_LIIn hAPP-KI mice, alcohol increases mPFC excitatory input, A{beta} plaque burden, and microglial activation, while impairing corticostriatal transmission and striatal cholinergic signaling. C_LIO_LIIn PS19 mice, alcohol enhances mPFC-to-striatum excitatory transmission and tau phosphorylation without altering local microglial activation or mPFC excitability. C_LIO_LIMicroglial depletion in wild-type mice recapitulates alcohol-induced glutamatergic changes in hAPP-KI mice, revealing a homeostatic role for microglia in regulating cortical excitatory balance. C_LI