Cross sensitization of diet and alcohol on binge behaviors and metabolic dysfunction

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Summary Cerebrovascular dysfunction is tightly linked to the deposition of amyloid plaques and neurofibrillary tangles in the brain; hallmarks of Alzheimer’s disease (AD). High fat diets (HFD) and chronic over-consumption of alcohol independently result in aberrant lipid metabolism which underlies the vascular dysfunction associated with obesity, type II diabetes, vascular dementia, and AD. While HFD and alcohol are both linked to the development of AD, there is limited information on how binge co-consumption of HFD and alcohol impact AD progression and associated cognitive decline. Our parent R01 utilizes a novel behavioral mouse model of binge co-consumption of HFD and alcohol which recapitulates clinical findings showing HFD increases alcohol intake and vice versa, providing a unique behavioral model to dissect the pathways that go awry with over-consumption of HFD and alcohol and how they impact the development of AD. HFD and chronic alcohol consumption have a profound impact on the speciation, composition, and function of plasma lipoproteins which modulate multiple metabolic pathways including systemic immune response, inflammation, glucose metabolism and oxidative stress. Lipoprotein function are mostly dominated by a handful of dynamic “scaffold” proteins that reside at the water- lipid interface, in particular apolipoprotein E (APOE) which has three isoforms—APOE2, APOE3, and APOE4. APOE4 is associated with elevated neuroinflammation and lower rates of cerebral glucose metabolism and carriers of APOE4 are at substantially elevated risk for early onset and increased severity of AD. We hypothesize that HFD and chronic alcohol consumption alter the speciation and compositional signatures of APOE-containing lipoproteins which exacerbates the neuroimmune response and accelerates cognitive decline and development of AD. Our specific aim is to characterize the impact of binge co-consumption of HFD and alcohol on the speciation and composition of APOE3 and APOE4-containing lipoproteins and how they modulate the development of AD. Utilizing transgenic mouse lines susceptible to Alzheimer’s Disease phenotypes with humanize APOE isoforms, we will determine how co-morbid high fat diet and alcohol binge consumption modulates memory function, insulin and glucose function, hippocampal neuroinflammation, and plasma lipoprotein speciation.