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卫生危机，尽管深入研究， 药物开发的努力。目前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的高调临床试验的失败， 神经元缠结，由Alois Alzheimer博士确定的AD的病理标志， 世纪前和广泛的研究和药物开发工作的重点，建议新的 在有效治疗AD之前， 疾病可以实现。 线粒体是一种动态的复杂细胞器，在生物学的许多方面都发挥着重要作用， 能量产生和中间代谢到细胞内信号传导和凋亡。这些广泛的功能 将安东定位为人类健康的核心参与者。在神经元中，线粒体和突触 紧密相连。除了线粒体在生物能量学中的核心作用外，它们还对 对维持细胞内Ca 2+稳态很重要。线粒体对Ca 2+的摄取有助于缓冲胞浆Ca 2 + 由神经元激活引起的瞬变，保护免受Ca 2+内流爆发的有害影响。 在基础条件下，正常神经元生理学需要Ca 2+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-Ca 2+稳态的关键细胞结构。 此外，人们逐渐认识到ERMCS在神经退行性疾病中的损伤，包括 AD. ERMCS和线粒体Ca 2+稳态如何改变，以及它们对疾病表型的贡献， 然而，体内环境还没有被很好地理解。本提案的目的是检验中心假设， APP代谢和ERMCS之间的相互作用指导ER-线粒体Ca 2+信号传导， 该过程有助于AD的病因学。为了检验这个假设，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.检测ERMCS蛋白在指导线粒体Ca 2+稳态中的作用 在疾病发病机制中介导APP功能。通过提供ERMCS参与的证据， 线粒体Ca 2+在APP细胞器、突触和生物体水平上的功能，这些研究将奠定 为今后研究ERMCS在正常脑生理中的调节和功能奠定了基础， 这将大大促进我们对线粒体和Ca 2+信号传导的基本作用的理解。 并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.