Intracellular organelle deficits driving Alzheimer's disease

阿尔茨海默病(AD)是一种以β-淀粉样蛋白聚集为特征的破坏性神经退行性疾病 (aβ)多肽，由过度磷酸化的tau组成的神经原纤维缠结，以及进行性认知能力丧失 功能。虽然人们对AD中淀粉样蛋白和tau的生化组成和结构了解很多， 对有害蛋白质产品的细胞内处理的关注相对较少，而更多 具体地说，上游细胞器功能缺陷如何加速疾病进程并直接 会导致记忆力受损。而神经元依靠专门的细胞器来执行特定的功能和 维持健康，特别是有几个与AD病理生理学有关，包括ER，这是重要的 蛋白质组装和细胞内钙信号；溶酶体，这是分解和 清除自噬菌体收集的细胞碎片和错误折叠的蛋白质；以及线粒体，这是 负责细胞的生物能量学(Muasty等人，2018年)。在维护全球业务中 神经元的生存能力，这些细胞器的功能是高度相互依赖的，它们通常是物理上的 相互耦合。尽管关系密切，但它们各自在AD中的作用通常是 已经被孤立地研究过。例如，有令人信服的研究详细描述了内质网、溶酶体或 AD中的线粒体功能障碍，但对这些之间的相互作用如何改变的了解却很少 细胞器可导致致病级联反应。这种孤立主义的做法可能会导致在 了解AD的关键过程和错过潜在的治疗机会。因此，总的目标是 这项研究旨在确定特定细胞器功能缺陷的潜在机制，并研究这一机制是如何 影响它们的相互作用，表征这如何加强AD的病理，并建立 这种级联反应被认为是一种治疗靶点。这将通过以下目标来实现：目标 I：确定AD相关的内质网功能中断是否扰乱溶酶体动力学和清除 聚集的蛋白质。目的II：确定过量的内质网钙离子释放破坏线粒体的机制 功能和退化。目的三：建立细胞内致病级联的上游驱动因素并确定 如果以内质网为靶点，动态平衡将解决溶酶体和线粒体缺陷。拟议的研究将有一个 对这一领域产生重大影响，因为它将提供关于错误聚集的蛋白质如何 在AD中积聚，并与改变的ER信号有关。此外，针对特定的细胞内 细胞器可能为AD提供有效的新的治疗策略。

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by aggregation of β-amyloid (Aβ) peptides, neurofibrillary tangles composed of hyperphosphorylated tau, and a progressive loss of cognitive function. While much is known regarding the biochemical composition and structure of amyloid and tau in AD, relatively less focus has been placed on the intracellular handling of detrimental protein products, and more specifically, how upstream deficits in organelle function can accelerate the disease process and directly contribute to memory impairments. While neurons rely on dedicated organelles to execute specific functions and sustain health, several in particular have been linked to AD pathophysiology, including the ER, which is important for protein assembly and intracellular calcium signaling; lysosomes, which are critical for breaking down and removing the cellular debris and misfolded proteins collected by authophagosomes; and mitochondria, which are responsible for the bioenergetics of the cell (Mustaly et al., 2018). In the global operations of maintaining neuronal viability, the functions of these organelles are highly inter-dependent, and they are often physically coupled to one another. Despite the close coupling, their respective roles in contributing to AD have typically been studied in isolation. For example, there are compelling studies detailing aspects of ER, lysosome, or mitochondrial dysfunction in AD, yet substantially less is understood about how altered interactions among these organelles can lead to pathogenic cascades. This isolationist approach may lead to critical oversights in understanding key processes in AD and missing potential therapeutic opportunities. Thus, the overall goal of this study is to identify mechanisms underlying deficiencies in specific organelle functions and examine how this affects their interactions, characterize how this potentiates AD pathology, and establish the upstream drivers of this cascade for consideration as a therapeutic target. This will be accomplished through the following Aims: Aim I: Determine if the AD-associated disruption in ER function disrupts lysosomal dynamics and clearance of aggregated proteins. Aim II: Determine the mechanism by which excess ER-Ca2+ release disrupts mitochondrial function and degradation. Aim III: Establish upstream drivers of intracellular pathogenic cascades and determine if targeting ER-homeostasis will resolve lysosomal and mitochondrial defects. The proposed study will have a significant impact on the field as it will provide new mechanistic information about how misaggregated proteins accumulate in AD and are associated with altered ER signaling. Moreover, targeting specific intracellular organelles may reveal effective new treatment strategies for AD.