Synpatic Autophagy in Alzheimer Disease

 描述（由申请人提供）： 阿尔茨海默病（AD）产生一种渐进性的大脑退化，慢慢地破坏受害者的认知能力。这种疾病给家庭和整个社会造成巨大的社会和经济负担。预计2017年将有超过20万名退伍军人被诊断患有痴呆症，其中AD是最常见的原因。AD的治疗选择仍然非常有限，并且没有治疗方法可以减缓疾病的无情进展。AD的病理学特征是存在由淀粉样前体蛋白（APP）衍生的淀粉样β（Aβ）组成的细胞外淀粉样斑块和微管相关蛋白tau的异常磷酸化，其导致神经元内缠结的形成。这些蛋白质沉积与皮质和海马体中神经元的急剧损失有关。然而，这些蛋白质积累和神经退行性变之间的机制关系是未知的。突触功能障碍和轴突终末丢失是AD中最早认识到的变化之一，这表明维持突触完整性的机制受损可能是病理学的基础或促成病理学。受损蛋白质的去除和替换（蛋白质稳态）是细胞维持功能结构（如线粒体）的主要机制。清除由两个相互关联的系统介导-泛素-蛋白酶体系统和自噬-溶酶体系统。有趣的是，最近的研究表明，在突触前末梢可能存在局部调节的蛋白质稳态程序。在我们的初步数据中，我们证明了自噬-溶酶体系统在突触处特异性上调以响应Aβ。在这个试点项目中，我们建议测试的假设，突触前自噬起着至关重要的作用，发生在AD的神经退行性变。为了验证这一假设，我们已经产生了两个突触前靶向的自噬分子调节因子-一个增强子和一个抑制子。我们建议，以确定改变突触前自噬的后果，在体外模型的AD以及小鼠模型的疾病。在拟议的研究结束时，我们希望有一个更好的理解突触前结构的自噬，以及这个过程如何与AD的神经退行性变。这些知识将有望帮助我们确定新的治疗目标，以减缓这种毁灭性疾病的进展。

 DESCRIPTION (provided by applicant): Alzheimer disease (AD) produces a progressive degeneration of the brain that slowly destroys a victim's cognitive abilities. This disease inflicts tremendous social and economic burden on families and society in general. It is projected that more than 200,000 Veterans will be diagnosed with dementia in 2017, with AD the most common cause. Therapeutic options for AD remain very limited and no treatments have been shown to slow the relentless progression of the disease. Pathologically AD is characterized by the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) and the abnormal phosphorylation of the microtubule associated protein tau that results in the formation of tangles inside neurons. These protein deposits are associated with a dramatic loss of neurons in the cortex and hippocampus. The mechanistic relationship between these protein accumulations and neurodegeneration is, however, unknown. Synaptic dysfunction and loss of axon terminals are among the earliest recognized changes in AD, suggesting that impairment of mechanisms that maintain integrity of synapses may underlie or contribute to pathology. Removal and replacement of damaged proteins (proteostasis) is a primary mechanism by which cells maintain functional structures such as mitochondria. Clearance is mediated by two interconnected systems-the ubitquitin-proteasome system and the autophagy-lysosome system. Interestingly, recent studies indicate that there may be locally regulated proteostasis programs at presynaptic terminals. In our preliminary data we demonstrate that the autophagy-lysosome system is upregulated specifically at synapses in response to Aβ. In this Pilot Project we propose to test the hypothesis that presynaptic autophagy plays a crucial role in the neurodegeneration that occurs in AD. To test the hypothesis, we have generated two presynaptically targeted molecular regulators of autophagy - one enhancer and one suppressor. We propose to determine the consequences of altering presynaptic autophagy on an in vitro model of AD as well as a murine model of the disease. At the end of the proposed studies we expect to have a better understanding of autophagy of presynaptic structures and how this process relates to neurodegeneration in AD. This knowledge will hopefully help us to identify novel targets for the treatments that slow the progress of this devastating disease.