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

饮食和酒精对暴饮暴食行为和代谢功能障碍的交叉敏感性

• 批准号: 10501123
• 负责人: Yuval Silberman
• 金额: $ 41.74万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10501123
• 关键词: Adopted; Alcohol consumption; Alcohols; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Apolipoprotein E; Behavior; Behavioral; Behavioral Model; Blood Vessels; Brain; Cell Surface Receptors; Cerebrospinal Fluid; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Complement; Consumption; Development; Diet; Disease Progression; Disease susceptibility; Enzymes; Ethanol; Genotype; Glucose; Goals; Heterogeneity; High Density Lipoproteins; High Fat Diet; Hippocampus (Brain); Histologic; Homeostasis; Human; Human body; Immune response; Impaired cognition; Impairment; Inflammation; Insulin; Link; Lipids; Lipoprotein (a); Lipoproteins; Memory; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Modeling; Molecular; Molecular Conformation; Monitor; Mus; Neurofibrillary Tangles; Neuroimmune; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Outcome Study; Oxidative Stress; Parents; Pathologic; Pathway interactions; Peripheral; Plasma; Protein Isoforms; Proteins; Proteome; Proteomics; Resolution; Risk; Risk Factors; Role; Scaffolding Protein; Senile Plaques; Severities; Short-Term Memory; Surface; System; Technology; Testing; Tissues; Transgenic Mice; Vascular Dementia; Vascular Diseases; Water; alcohol use disorder; binge drinking; binge type behavior; blood glucose regulation; cerebrovascular; chronic alcohol ingestion; clinically relevant; cognitive development; comorbidity; disease phenotype; early onset; glucose metabolism; glucose tolerance; human model; improved; insulin signaling; insulin tolerance; lipid metabolism; lipid transport; lipidomics; liquid chromatography mass spectrometry; morris water maze; mouse model; nanosized; neuroinflammation; new therapeutic target; novel; novel therapeutic intervention; particle; pleiotropism; protein complex; response; scaffold

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.

总结 脑血管功能障碍与脑内淀粉样斑块和神经纤维缠结的沉积密切相关。 大脑;阿尔茨海默病（AD）的标志。高脂饮食（HFD）和长期过度饮酒 独立地导致脂质代谢异常，这是与以下相关的血管功能障碍的基础： 肥胖、II型糖尿病、血管性痴呆和AD。虽然HFD和酒精都与发展有关， 关于HFD和酒精的过度共同消费如何影响AD进展的信息有限， 相关的认知能力下降我们的亲本R 01利用了一种新的狂欢共消费行为小鼠模型 HFD和酒精的关系，这概括了临床研究结果，表明HFD会增加酒精摄入量，反之亦然， 提供了一个独特的行为模型来剖析HFD过度消费的途径， 酒精及其对AD发展的影响HFD和慢性酒精消费有着深刻的 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位于水中的动态“支架”蛋白质控制- 脂质界面，特别是载脂蛋白E（APOE），其具有三种亚型-APOE 2、APOE 3和APOE 4。 APOE 4与神经炎症升高和脑葡萄糖代谢率降低相关， APOE 4携带者AD早发和严重程度增加的风险显著升高。我们假设 HFD和慢性饮酒改变了含APOE的细胞的形态和组成特征， 脂蛋白，加剧神经免疫反应，加速认知能力下降和发育 的AD。我们的具体目标是描述HFD和酒精的狂欢共同消费对 含APOE 3和APOE 4脂蛋白的形态和组成，以及它们如何调节 AD的发展。利用易患阿尔茨海默病表型的转基因小鼠品系， 人源化载脂蛋白E同种型，我们将确定高脂饮食和酗酒是如何共病 调节记忆功能、胰岛素和葡萄糖功能、海马神经炎症和血浆 脂蛋白形态