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• W2981154345 abstract "Alzheimer's disease (AD) is characterized by abnormal protein aggregates, calcium dyshomeostasis, and synaptic deficits. To maintain normal cellular activity, tight coordination across key organelles is required; conversely, deficits in one organelle system can lead to cascading pathology within the cellular network. Here, we probe the inter-related roles of lysosomes, autophagosomes, the ER and mitochondria to determine how altered upstream ER calcium homeostasis disrupts pH-sensitive organelles and lysosome-autophagosome handling of pathogenic protein species, and feeds into mitochondrial stress and synaptic defects. We combine fluorescent live cell imaging of intracellular processes, incorporating lysosome-targeted pH sensitive dyes, genetically-encoded calcium indicators, autophagosome sensors, and mitochondrial membrane indicators in model cells, neurons from AD mouse models, and in human neurons derived from AD patients. This is combined with immunoassays and electrophysiology in mouse and human neurons. In AD neurons, the early reduction in several key vacuolar ATPase (vATPase) subunits in the lysosome proton pump is associated with a less acidic organelle and impaired clearance of mature autophagosomes. Excessive calcium release from the ER further disrupts lysosomal pH and contributes to accumulation of pathogenic protein species such as phospho-tau in the mouse and human AD neurons. Mitochondrial functions are also affected as a result of ER calcium dyshomeostasis, which is thought to be the upstream driver of the protein handling deficits, metabolic stress, and synaptic impairment observed in these models. Acute and sub-chronic treatment with calcium channel inhibitors which normalize ryanodine receptor function restores normal expression of the vATPase subunits and acidic lysosomal pH, autophagosome clearance, metabolic homeostasis, and synaptic function, in both the mouse and human AD neurons. We hypothesize that, prior to overt histopathology or cognitive deficits, altered Ca2+ signaling disrupts vATPase ion exchange within acidic organelles, such as lysosomes and synaptic vesicles, and initiates pathogenic cascades resulting in abnormal protein aggregation, synaptic signaling defects, and metabolic stress. This pathway is evident in human neurons from AD patients and replicated in several mouse models of AD, thus supporting the targeting of upstream calcium signaling abnormalities as a viable therapeutic strategy for AD." @default.
• W2981154345 created "2019-10-25" @default.
• W2981154345 creator A5077428900 @default.
• W2981154345 date "2019-07-01" @default.
• W2981154345 modified "2023-09-28" @default.
• W2981154345 title "P4-501: EARLY-STAGE DEFECTS IN LYSOSOMAL FUNCTIONS INITIATE PROTEIN MISHANDLING IN NEURONS FROM AD MOUSE MODELS AND NEURONS FROM HUMAN PATIENTS" @default.
• W2981154345 doi "https://doi.org/10.1016/j.jalz.2019.08.047" @default.
• W2981154345 hasPublicationYear "2019" @default.
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