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

摘要 脑血管功能障碍与淀粉样斑块和神经原纤维缠结的沉积密切相关。 大脑；阿尔茨海默病(AD)的特征。高脂肪饮食(HFD)和慢性过度饮酒 独立导致脂代谢异常，这是与 肥胖、II型糖尿病、血管性痴呆和阿尔茨海默病。而HFD和酒精都与发育有关 在阿尔茨海默病中，关于狂饮HFD和酒精共同消费如何影响AD进展和 相关的认知能力下降。我们的父母R01利用了一种新的狂欢共同消费的行为小鼠模型 总结了HFD和酒精的临床发现，表明HFD增加酒精摄入量，反之亦然， 提供了一个独特的行为模型来剖析过度摄入HFD和 酒精及其如何影响阿尔茨海默病的发展。HFD和慢性饮酒有深远的关系 对调节多种代谢的血浆脂蛋白的形态、组成和功能的影响 途径包括全身免疫反应、炎症、葡萄糖代谢和氧化应激。 脂蛋白的功能主要由少数动态的“支架”蛋白质主导，它们驻留在水中- 脂质界面，特别是载脂蛋白E(APOE)，它有三种亚型--APOE2、APOE3和APOE4。 载脂蛋白E4与升高的神经炎症和较低的大脑葡萄糖代谢率和 APOE4携带者早发和AD严重程度增加的风险显著增加。我们假设 高脂血症和长期饮酒改变了含载脂蛋白E的形态和组成特征 脂蛋白，加剧神经免疫反应，加速认知衰退和发育 公元一代的。我们的具体目标是表征狂饮HFD和酒精共同消费对 含APOE3和APOE4的脂蛋白的形态和组成及其如何调节 AD的发展。利用转基因小鼠对阿尔茨海默病易感表型 将载脂蛋白E亚型人性化，我们将确定高脂肪饮食和酗酒是如何共病的 调节记忆功能、胰岛素和血糖功能、海马神经炎症和血浆 脂蛋白物种形成。

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.