Date of Award
Doctor of Philosophy (PhD)
Jonathan D. Geiger
Neurodegenerative disorders are affecting increasingly numbers of humans, especially in our ever increasingly aged population. Here, I attempt to better understand how endolysosomes contribute to pathological features in two neurodegenerative disorders including Alzheimer's Disease (AD) and HIV associated neurocognitive disorders (HAND) and to the regulation of intracellular calcium levels in cultured neurons.
According to our previous in vivo studies that elevated circulating ApoB cholesterol per se contributed to the pathogenesis of sporadic AD by affecting endolysosomes, we tested the hypothesis that; ApoB containing cholesterol altered endolysosome structure & function and contributed to AD-like pathological development in primary cultured neurons. Besides, HIV-1 protein Tat is a causative factor for HAND because it induces neurotoxicity and A-beta elevation. Based on the facts that endolysosomes are not only implicated into neurotoxicity and endocytosis of HIV-1 Tat, but also into amyloidogenesis, we tested the hypothesis that; HIV-1 Tat directly altered endolysosome structure & function, which contributed to neurotoxicity and the development of AD-like pathology in primary cultured neurons. Our data together demonstrated that ApoB containing LDL cholesterol and HIV-1 Tat both enlarged endolysosomes, elevated endolysosome pH, reduced endolysosome enzymes' activity, enhanced BACE-1 activity and raised A-beta production accompanied by endolysosome accumulation of APP, BACE-1 and A-beta. Our data strongly suggest that altered endolysosome structure & function could contribute to AD-like pathological development in AD & HAND and additionally contribute to neurotoxicity in HAND.
As `acidic' calcium stores, little is known about how endolysosome calcium is released and how this release contributes to calcium signals both spatially and temporally. Here, we found in primary cultured hippocampal neurons that calcium released from acidic calcium stores triggered calcium influx, which we termed `acidic store-operated calcium entry' (aSOCE), similar to classical store-operated calcium entry (SOCE). Moreover, we found that the aSOCE was mediated by cell surface redistribution of N-type calcium channels, which is regulated by lysosome exocytosis. Our data suggest that lysosome exocytotic insertion of N-type calcium channels might underlie this novel aSOCE in neurons. Such findings could provide a new insight into the spatiotemporal complexity of calcium signals and fundamental calcium-dependent cellular responses.
Hui, Liang, "The Role Of Endolysosomes In Models Of Neurodegenerative Disorders And In Regulating Levels Of Intracellular Calcium" (2012). Theses and Dissertations. 1249.