Interplay between amyloid precursor protein metabolism and ER-mitochondria contact

阿尔茨海默病(AD)仍然是一个迫在眉睫的公共健康危机，尽管有大量的研究和 医药发展努力。目前还没有有效的治疗方案可以阻止 疾病过程。最近针对淀粉样斑块和淀粉样蛋白的高调临床试验失败 神经原纤维缠结，阿尔茨海默博士发现的阿尔茨海默病的病理特征 百年前和重点广泛的研究和药物开发努力，表明新的 在有效治疗阿尔茨海默病之前，有必要对AD的发病机制进行描述 疾病是可以实现的。 线粒体是动态而复杂的细胞器，在生物学的许多方面都扮演着重要的角色，从 能量的产生和细胞内信号和细胞凋亡的中间代谢。这些广泛的功能 将线粒体定位为人类健康的核心角色。在神经元中，线粒体和突触 紧密联系在一起。除了线粒体在生物能量学中的核心作用外，它们还至关重要 对维持细胞内钙稳态很重要。线粒体摄取钙有助于缓冲胞浆钙 由神经元激活产生的瞬变，保护免受钙离子内流爆发的有害影响。 在基础状态下，正常的神经生理需要钙离子进入线粒体。急诊室- 线粒体接触位点(ERMCS)被认为是调节线粒体-钙稳态的关键细胞结构。 此外，在神经退行性疾病中出现了对ERMCS损伤的认识，包括 广告。ERMCS和丝裂原-钙稳态如何改变及其在疾病表型中的作用 然而，活体环境并没有得到很好的理解。这项提议的目标是检验核心假设，即 APP代谢和ERMCS之间的相互作用指导ER-线粒体钙信号转导，并且 这一过程有助于AD的病因学研究。为了验证这一假设，我们建议实现以下目标 本探索性项目的具体目标：目标1.检查果蝇AD中ERMCS形成的缺陷 模型和AD患者来源的细胞；目的2.测试ERMCS蛋白在引导有丝分裂-钙稳态中的作用 在介导APP在疾病发病机制中的作用。通过提供ERMCS参与的证据和 这些研究将为APP在细胞器、突触和有机体水平上发挥作用奠定基础 为未来研究ERMCS在正常脑生理中的调节和功能奠定基础， 这将极大地促进我们对线粒体和钙信号的基本作用的理解 治疗阿尔茨海默病，最终提供新的治疗策略。

Alzheimer's disease (AD) remains a looming public health crisis, despite intensive research and pharmaceutical development efforts. No effective treatment option is currently available that can halt the disease process. The recent failures of high-profile clinical trials targeting the amyloid plaques and neurofibrillary tangles, the pathological hallmarks of the AD identified by Dr. Alois Alzheimer more than a century ago and the focus of extensive research and pharmaceutical development efforts, suggest that new directions in delineating the pathogenic mechanisms of AD are warranted before effective treatment of the disease can be achieved. Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from energy production and intermediary metabolism to intracellular signaling and apoptosis. These broad functions position mitochondrion as a central player in human health. In neurons, mitochondria and synapses are intimately linked. In addition to the central role of mitochondria in bioenergetics, they are also critically important for maintaining cellular Ca2+ homeostasis. Ca2+ uptake by mitochondria helps buffer cytosolic Ca2+ transients arising from neuronal activation, protecting against the detrimental effects of bursts of Ca2+ influx. Under basal conditions, Ca2+ entry into mitochondria is needed for normal neuronal physiology. The ER- mitochondria contact site (ERMCS) are recognized as key cellular structures regulating mito-Ca2+ homeostasis. Moreover, there is an emerging recognition of ERMCS impairment in neurodegenerative diseases including AD. How ERMCS and mito-Ca2+ homeostasis are altered, and their contribution to disease phenotypes in in vivo settings, however, are not well understood. The goal of this proposal is to test the central hypothesis that an interplay between APP metabolism and ERMCS directs ER-mitochondrial Ca2+ signaling, and that defects in this process contributes to the etiology of AD. To test this hypothesis, we propose to achieve the following Specific Aims in this exploratory project: Aim 1. Examine defects in ERMCS formation in a Drosophila AD model and AD patient derived cells; Aim 2. Test the roles of ERMCS proteins that direct mito-Ca2+ homeostasis in mediating APP function in disease pathogenesis. By providing evidence for the involvement of ERMCS and mito-Ca2+ in APP function at the organellar, synaptic, and organismal levels, these studies will lay the foundation for future studies addressing the regulation and function of ERMCS in normal brain physiology, which will significantly advance our understanding of the fundamental roles of mitochondria and Ca2+ signaling in AD and ultimately offer novel therapeutic strategies.