Adolescent Alcohol in 5xFAD Mouse Model Accelerates Neuroinflammation and Alzheimer's Disease Pathology Across Aging

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ABSTRACT. Adolescent Alcohol in 5xFAD Mouse Model Accelerates Neuroinflammation and Alzheimer’s Disease Pathology Across Aging. Our laboratory and others find adolescent intermittent ethanol (AIE; 2-days EtOH/2-days NO EtOH during adolescence) primes and accelerates adult Alzheimer’s disease (AD)-related degeneration and cognitive deficits that persist in the absence of continued adult EtOH exposure. Our premise for this proposal is built on priming of common mechanisms of pathology, including chronic neuroinflammation and loss of basal forebrain cholinergic neurons (BFCNs). This proposal will test the overarching hypothesis that AIE-induced persistent, life-long loss of BFCNs and chronic neuroinflammation contribute to the onset and progression of AD-associated neuropathology and cognitive decline across aging. This hypothesis is built on our preliminary findings, including (1) AIE increase of receptor for advanced glycation end-products (RAGE) and other neuroinflammatory molecules, induction of AD-associated genes, and reductions of BFCNs, hippocampal neurogenesis, and cognitive function in adulthood; (2) increased RAGE-neuroinflammation and AD-like pathology in post-mortem human AUD brain samples of individuals with an adolescent age of drinking onset. We recently discovered that AIE accelerates adult BFCN neurodegeneration, neuroinflammation, and accumulation of amyloid-β (Aβ) in a genetic mouse model of AD. We developed an innovative mouse model using the 5xFAD genetic mouse model of AD, which recapitulates the dual Aβ accumulation and neurodegeneration observed in human AD, crossbred with ChAT- Cre mice to investigate interactions of AIE with Aβ accumulation across aging on BFCN and hippocampal pathology. Aim 1 tests the hypothesis that AIE accelerates AD-associated neuropathology in the aging brain of ChAT-Cre::5xFAD mice. We expect AIE will accelerate neuroinflammation, neurodegeneration, and AD-associated pathology across ages. Aim 2 tests the hypothesis that AIE-induced basal forebrain RAGE- neuroinflammatory signaling causes BFCN loss, neuroimmune signaling, AD pathology, and cholinergic dysfunction in the aging brain of ChAT-Cre::5xFAD mice. AIE induces RAGE-neuroinflammatory signaling and loss of BFCNs that persists into adulthood. We expect RAGE-neuroinflammatory signaling contributes to AD-associated BFCN pathology. Aim 3 tests the hypothesis that chronic activation of basal forebrain cholinergic activity during AIE prevents loss of hippocampal activity, neurogenesis, and cognitive function, and reduces AD-associated neuropathology in the aging brain of ChAT-Cre::5xFAD mice. AIE increases hippocampal neuroinflammation, reduces neurogenesis, and impairs cognition in adulthood that is prevented by anti-cholinesterase drugs. We expect BFCN activation to both identify cholinergic involvement and recover AD-associated hippocampal pathology. The proposed studies will link early life insults (i.e., adolescent binge drinking) to AD-like neurodegeneration and dementia in the aging brain, and identify potential therapeutics.