Role of BMP Signaling in the Aging Brain R01 AG054429

衰老是发生散发性阿尔茨海默病（sAD）的主要风险因素，这表明， 衰老过程与疾病的病理生理学有关。衰老过程是高度 变量，一些老年人发展非退行性认知障碍，而其他人 是有弹性的这种异质性的生物学基础尚不清楚。然而，衰老与 生物化学和形态学的变化，可能会揭示这两个表型 年龄的异质性和与年龄相关的AD易感性。特别是， 海马结构和连接与衰老有关。在这些变化中， 齿状回（DG）神经发生下降，海马表现下降- 依赖性认知任务大脑中的BMP信号随着年龄的增长而急剧增加， 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， 认知. BMP信号传导和神经发生在AD中也都显著改变。但 尚不清楚AD中BMP信号传导和神经发生的变化是否是AD的恶化， 衰老过程，或者说是由于不相关的机制。这一拟议补充的目标是 是利用我们正在进行的研究中开发的知识和工具， BMP信号在衰老大脑中的作用，以确定这一信号通路在发育中的作用。 的AD。仅次于年龄，人类载脂蛋白E（hAPOE）基因型是已知最强的风险 sAD的因素。此外，在衰老小鼠中，ε4亚型的神经元表达导致神经元凋亡。 丧失和受损的学习和记忆，APOE调节海马神经发生。的 BMP信号和APOE的老化相关增加对 认知和对神经发生的影响表明， 在BMP信号传导、APOE基因型和sAD的发展中。具体来说，我们假设 大脑中与衰老相关的BMP信号的增加使神经元易于受到 APOE 4与AD的发展有关，并且它至少部分地解释了为什么衰老是AD发病的原因。 sAD的最大危险因素。我们将使用我们从sAD患者中获得的iPSC系来探索 APOE基因型与BMP信号转导对tau蛋白磷酸化、淀粉样蛋白磷酸化 分泌和神经突保存，以及增加钙内流后神经元存活的影响。 来源于iPSC的神经元。我们还将研究BMP信号在发育中的作用 病理学和行为学变化。

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.