Chronic alcohol exposure produces pathology-dependent corticostriatal circuit remodeling in Aβ- and tau-based mouse models of Alzheimer's disease.

Chronic alcohol consumption is a major risk factor for Alzheimer's disease (AD), yet how alcohol exposure alters neural circuits under distinct pathological conditions remains poorly understood. Here, we used a humanized Aβ knock-in model (hAPP-KI) and a tauopathy model (PS19) to test how the same alcohol exposure affects distinct pathological contexts. In hAPP-KI mice, alcohol exposure increased cortical Aβ burden, enhanced excitatory synaptic transmission in the medial prefrontal cortex (mPFC), and reduced glutamatergic transmission from the mPFC to the dorsomedial striatum (DMS). In contrast, in PS19 mice, alcohol exposure increased tau phosphorylation and elevated mPFC-to-DMS glutamatergic transmission without altering local cortical excitatory input. Alcohol exposure was also associated with distinct microglial responses across pathological contexts. To assess microglial contributions to cortical excitatory regulation, we depleted microglia in wild-type mice and observed enhanced cortical glutamatergic transmission. Together, these findings suggest pathology-dependent circuit remodeling and microglial responses associated with alcohol exposure in AD models.