Role of BMP Signaling in the Aging Brain R01 AG054429

BMP 信号传导在大脑衰老中的作用 R01 AG054429

• 批准号: 10121093
• 负责人: JOHN A KESSLER
• 金额: $ 35.98万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10121093
• 关键词: AD transgenic mice; Address; Age; Age-Months; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid deposition; Apolipoprotein E; Astrocytes; Behavioral; Biochemical; Biological; Brain; CRISPR/Cas technology; Calcium; Cell Death; Cognition; Cognitive deficits; Development; Disease; Etiology; Exercise; Exhibits; Functional disorder; Genes; Genotype; Glutamates; Goals; Grant; Heterogeneity; Heterozygote; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Injections; Intraventricular Infusion; Ionophores; Knowledge; Lead; Learning; Link; Mediating; Memory; Morphology; Mus; Neurites; Neurons; Pathologic; Pathology; Patients; Performance; Phenotype; Phosphotransferases; Predisposition; Process; Protein Isoforms; Risk Factors; Rodent; Role; Signal Pathway; Signal Transduction; Structure; Synapses; System; Time; Toxic effect; Transgenic Organisms; adeno-associated viral vector; age effect; age related; aged; aging brain; axonopathy; bone morphogenetic protein 4; cerebral atrophy; cognitive task; dentate gyrus; excitatory neuron; functional decline; gene product; in vivo; induced pluripotent stem cell; inhibitor/antagonist; insight; mouse model; neurogenesis; neuron loss; neuronal survival; nonhuman primate; overexpression; p38 Mitogen Activated Protein Kinase; preservation; prevent; stem cells; tau Proteins; tau phosphorylation; tau-1; tool; β-amyloid burden

Aging is the leading risk factor for developing sporadic Alzheimer’s disease (sAD) suggesting that the aging process is linked to the pathophysiology of the disease. The aging process is highly variable, and some aged individuals develop non-degenerative cognitive impairment while others are resilient. The biological basis of this heterogeneity is unknown. However, aging is associated with biochemical and morphological changes that may shed insight into the both the phenotypic heterogeneity in aging and the age-related susceptibility to AD. In particular, changes in hippocampal structure and connectivity are associated with aging. Among these changes is a decline in neurogenesis in the dentate gyrus (DG) with decreased performance on hippocampus- dependent cognitive tasks. BMP signaling in the brain increases dramatically with age, and we have been exploring the hypothesis that this underlies aging-related changes neurogenesis and cognition. BMP signaling and neurogenesis are also both altered significantly in AD. However, it is unclear whether changes in BMP signaling and in neurogenesis in AD are an exacerbation of the aging process or rather due to unrelated mechanisms. The goal of this proposed supplement is to use both the knowledge and the tools developed as part of our ongoing studies of the role of BMP signaling in the aging brain to define the role of this signaling pathway in the development of AD. Second to age, the human apolipoprotein E (hAPOE) genotype is the strongest known risk factor for sAD. Further, in aging mice, neuronal expression of the ε4 isoform results in neuron loss and impaired learning and memory, and APOE regulates hippocampal neurogenesis. The convergence of the effects of the aging related increase in BMP signaling and of APOE on cognition and on neurogenesis suggest possible interactions between the aging related increase in BMP signaling, APOE genotype, and the development of sAD. Specifically, we hypothesize that the aging related increase in BMP signaling in brain predisposes neurons to the effects of APOE4 and to development of AD, and that that it explains, at least in part, why aging is the greatest risk factor for sAD. We will use the iPSC lines we derived from sAD patients to explore interactions between APOE genotype and BMP signaling on tau phosphorylation, amyloid ß secretion, and neurite preservation, and on neuronal survival after increasing calcium influx in neurons derived from the iPSCs. We also will examine the role of BMP signaling in development of pathology and of behavioral changes in 5XFAD mice.

衰老是发生散发性阿尔茨海默病 (sAD) 的主要危险因素，这表明 衰老过程与疾病的病理生理学有关。 变量，一些老年人出现非退行性认知障碍，而另一些人则出现非退行性认知障碍 这种异质性的生物学基础尚不清楚，但与衰老有关。 生化和形态学的变化可能有助于深入了解表型 衰老的异质性和与年龄相关的 AD 易感性，特别是 AD 的变化。 海马结构和连接性与衰老有关。 齿状回（DG）神经发生下降，海马体表现下降 大脑中依赖的 BMP 信号随着年龄的增长而急剧增加，而且我们 一直在探索这一假设，即这是与衰老相关的神经发生变化的基础， 然而，AD 中的 BMP 信号传导和神经发生也发生了显着改变。 目前尚不清楚 AD 中 BMP 信号传导和神经发生的变化是否会加剧 衰老过程或更确切地说是由于不相关的机制。本提议补充的目标。 是利用我们持续研究的一部分所开发的知识和工具 衰老大脑中的 BMP 信号传导确定了该信号传导途径在发育中的作用 除了年龄之外，人类载脂蛋白 E (hAPOE) 基因型是已知的最强的 AD 风险。 此外，在衰老小鼠中，ε4亚型的神经表达导致神经元的形成。 APOE 调节海马神经发生。 与衰老相关的 BMP 信号传导和 APOE 增加的影响趋同 认知和神经发生表明衰老相关增加之间可能存在相互作用 BMP 信号传导、APOE 基因型和 sAD 的发展。 大脑中与衰老相关的 BMP 信号传导增加使神经元容易受到 APOE4 与 AD 的发展有关，并且它至少部分地解释了为什么衰老是 我们将使用从 SAD 患者身上获得的 iPSC 系来探索。 APOE 基因型和 BMP 信号在 tau 磷酸化、淀粉样蛋白 ß 上的相互作用 分泌、神经突保存以及增加钙流入后的神经元存活 我们还将研究 BMP 信号传导在发育中的作用。 5XFAD 小鼠的病理学和行为变化。