Programming amylin secretion to slow brain aging - an animal model

编程胰淀素分泌以减缓大脑衰老——动物模型

• 批准号: 9412623
• 负责人: Florin Despa
• 金额: $ 67.17万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412623
• 关键词: APP-PS1; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloidosis; Animal Model; Behavior; Biological; Biological Neural Networks; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Cerebrum; Data; Deposition; Development; Diabetes Mellitus; Disease Progression; Early Onset Familial Alzheimer' s Disease; Feasibility Studies; Functional disorder; Genes; Goals; Heart failure; Hormones; Human; Impaired cognition; Individual; Injury; Insulin; Intravenous; Intravenous infusion procedures; Investigation; Islets of Langerhans; Late Onset Alzheimer Disease; Link; Longevity; Mediating; Microglia; Molecular; Mus; Neuraxis; Neuronal Dysfunction; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathogenesis; Pathology; Peripheral; Pre-Clinical Model; Protein Isoforms; Rattus; Structure of beta Cell of islet; Synapses; Testing; Time; Transgenes; Transgenic Mice; aging brain; amyloid peptide; apolipoprotein E-4; behavior change; beta amyloid pathology; cognitive performance; design; diabetic patient; early onset; in vivo; islet amyloid polypeptide; mouse model; non-diabetic; novel; overexpression; proteostasis; transgene expression; transgenic model of alzheimer disease; uptake

PROJECT SUMMARY Proteostasis dysfunction of pancreatic β-cells results in accumulation of oligomerized amylin within pancreatic islets, which is a hallmark of type-2 diabetes. We recently showed that oligomerized amylin also incorporates into the brain blood vessel walls, forms neuritic deposits and co-localizes with Alzheimer's disease (AD) - amyloid peptides (Aβ) as mixed Aβ-amylin plaques in brains of individuals with late-onset AD as well as familial early-onset AD. It is unknown whether cerebral amylin deposits are a consequence of AD or type-2 diabetes, or a “hidden” trigger of AD. Moreover, we found that overexpressing human amylin within pancreatic islets in rats induces systemic amylin dyshomeostasis, brain amylin accumulation, microglia activation and behavior changes. Furthermore, elevated human amylin in the periphery greatly accelerates behavior changes in a rat model of AD pathogenesis. These findings suggest the hypothesis that amylin dyshomeostasis in pancreatic islets and subsequent secretion of oligomerized amylin in the blood can affect the progression of AD by compromising the ability of microglia to efficiently clear Aβ and by inducing mixed Aβ-amylin pathology. Thus, ameliorating amylin dyshomeostasis in the periphery can limit the progression of AD. The overarching goal of this proposal is to test our hypothesis and investigate molecular mechanisms underlying the interaction of amylin with Aβ pathology. We will accomplish this goal by characterizing novel transgenic mice with inducible and reversible expression of human amylin in the pancreas (HuAmy line). We will carefully dissect proteostasis dysfunction of pancreatic β-cells in the periphery and the consequent liability it imposes on the central nervous system. We will also cross HuAmy line and 85Dbo line to generate APP/PS1 transgenic mice with regulated expression of human amylin in the periphery. We predict that turning off the human amylin transgene expression at early time points during aging mitigates the disease progression in HuAmy:APP/PS1 mice by limiting the blood-brain barrier injury and rescuing the ability of microglia to clear Aβ. This investigation using novel regulated amylin expression represents the most direct in vivo approach to rigorously test the involvement of peripheral amylin in the biological pathways of AD pathogenesis. The completion of these aims will elucidate the interplay of amylin dyshomeostasis with the progression of Aβ pathology and whether ameliorating amylin dyshomeostasis in the periphery can reduce or reverse AD in a preclinical model. We believe that the proposed investigation fills significant gaps in our understanding of the molecular link between type-2 diabetes and AD.

项目摘要 胰腺β细胞的蛋白质抑制功能障碍导致寡聚链淀粉在胰腺内的积累 胰岛，这是2型糖尿病的标志。我们最近表明，低聚淀粉蛋白也掺入 进入脑血管壁，形成神经质沉积物，并与阿尔茨海默氏病（AD）-- 淀粉样蛋白（Aβ）作为滞后AD和家族个体的大脑中的Aβ-淀粉斑作为混合的Aβ-淀粉斑块 早发广告。尚不清楚脑淀粉蛋白沉积是AD或2型糖尿病的结果， 或AD的“隐藏”触发器。此外，我们发现在胰岛中过度表达人淀粉 大鼠诱导全身性淀粉蛋白异神经素，脑淀粉纤维积累，小胶质细胞激活和行为 更改。此外，外围的人氨基蛋白升高大大加速了大鼠的行为变化 AD发病机理的模型。这些发现表明胰腺中的氨基氨基异质体的假设 胰岛和随后在血液中寡聚淀粉蛋白的分泌会影响AD的进展 损害小胶质细胞有效清除Aβ并通过诱导的混合Aβ-淀粉蛋白病理学的能力。那， 在周围的改善淀粉蛋白异质症可以限制AD的进展。总体目标 该建议是检验我们的假设，并研究了相互作用的分子机制 具有Aβ病理学的淀粉蛋白。我们将通过诱导的新型转基因小鼠来实现这一目标 胰腺中人氨基蛋白的可逆表达（Huamy Line）。我们将仔细剖析蛋白质 外围胰腺β细胞功能障碍以及中枢神经系统所带来的责任 系统。我们还将越过Huamy Line和85DBO线，以生成APP/PS1转基因小鼠，并具有调节 人淀粉素在周围的表达。我们预测关闭人淀粉蛋白转化 衰老期间早期的表达减轻了Huamy的疾病进展：APP/PS1小鼠 限制了血脑屏障损伤并挽救小胶质细胞清除Aβ的能力。此调查使用 新型调节的链淀粉表达代表了严格测试的最直接的体内方法 周围淀粉素参与AD发病机理的生物学途径。这些目标的完成 将阐明氨基蛋白异神经素与Aβ病理发展的相互作用以及是否是否 在外周种中改善淀粉蛋白异质症可以减少临床前模型中的AD或反向AD。我们 认为拟议的调查填补了我们对分子联系之间的显着空白 2型糖尿病和广告。