Alzheimer's disease, filling in pieces of the big puzzle

grantor: University of TorontoAlzheimer's disease (AD) has been proposed to result from interactions between susceptibility genes and environmental factors. This thesis examines such potential interactions between aluminum exposure, presenilin (PS) mutations and amyloid deposition. Differences in uptake and toxicity between various aluminum salts were examined. Aluminum toxicity did not always correlate with uptake in neurons and astrocytes. I hypothesised that amyloid precursor protein (APP) secretion may be altered following aluminum insults. In response to aluminum exposure, both neurons and astrocytes increased APP secretion. These data were the first evidence for an interaction between aluminum and APP. I tested the hypothesis that the effect of PS mutations on APP may derive from the mislocation of mutated PS. The distribution of mutant PS1 was examined in dissociated cultures of hippocampal neurons and in fibroblasts derived from AD. Confocal microscopy revealed that PS was localised to the endoplasmic-reticulum-Golgi intermediate compartment of both cell lines but that the distribution of mutant presenilin was identical to that of wild-type PS1 (wtPS1). Cells expressing PS1 mutations have been shown to have an increased susceptibility to excitotoxic insults. In addition, the possibility that fibroblasts derived from AD patients would have a decreased viability when exposed to aluminum compared to those expressing wtPS1 was examined. No difference in toxicity was obtained between fibroblasts bearing wtPS1 or mutants presenilin in response to aluminum exposure. However, cells expressing PS1 mutants had the greatest levels of aluminum uptake which is the first evidence for a link between aluminum and the presenilins. Artificial "plaques" were created from aggregated synthetic Aß peptides to test the hypothesis that senile amyloid plaques are toxic to neurons. These plaques inhibited neuronal adhesion and neurite extension without affecting cell viability. No effects were obtained in astrocytes growing under these same conditions. Taken together these results provide a compelling link for the interaction between aluminum exposure and PS. The increasing prevalence of AD associated with our aging population places a heavy burden on our society. Further insights into the role played by APP, aluminum, and PS on the AD neurodegenerative process will facilitate the development of new treatments for this debilitating disease.Ph.D