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

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.