Investigating the roles of endogenous APP family members in stress signaling and aging

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Previous studies from our labs suggest that APPsα, which is generated via cleavage of APP by the activity of α-secretase along the secretory pathway exerts potent neuroprotective effects via modulalion of gene expression, as well as by antagonizing oxidative stress and other types of neurotoxic stress stimuli, thereby inhibiting stress-triggered cell death. We have also shown that the biochemical processing of endogenous APP is downregulated during aging of non-transformed human fibroblasts, resulting in a potently reduced secretion of APPsα. Based on these observations, we aim to 1) further investigate the potential physiological roles of APP and APLPs and their cleavage products in neuroprotection, 2) analyze the funclional consequences of APP/APLP depletion on gene expression and cellular vulnerability to neurotoxic stress, and 3) dissect the role of APP processing during neuronal and brain aging and its link to age-associated stress signaling pathways, alterations in gene expression, and oxidative changes.