Project 460603

The aging brain goes through several changes, at the cellular and molecular levels, associated with protein removal through autophagy, lead to the aggregation of misfolded/damaged proteins and eventually to the disruption of the nuclear membrane. The disruption of these cellular events has also been linked with age-related diseases, such as Alzheimer's disease (AD). Much of the brain failure during AD is related with the B-amyloid peptide resulting from the incorrect cleavage of the amyloid precursor protein, that has been associated with dysfunction of the presenilin-1 (PS-1) protein. Alterations in the PS-1 gene have been related with nuclear membrane disruption and autophagy impairment. A mRNA transcripts screen in our laboratory identified a PS-1 splicing variant (SV) that is highly expressed in AD brain samples. The role of PS-1(SV) during AD and aging is unknown. Since current AD pharmacological therapies are not effective, there is critical need to find treatment strategies. One promising alternative is caloric restriction (CR), a modified dietary regime, which has been shown to increase autophagy, reduce risk of AD and extend lifespan in various species. A new class of compounds called CR mimetics (CRms), which mimic the effects of CR, have been identified. The hypothesis of my research is that PS-1(SV) facilitates age- and AD-related phenotypes, and that CRms will counteract the effects of PS-1(SV) by stimulating autophagy and therefore improve cellular phenotypes. I will test my hypothesis expressing PS-1(SV) in Caenorhabditis elegans strains and mammalian cell cultures, with a focus on the nuclear membrane integrity autophagy markers. The effects of PS-1(SV) will be compared to those of PS-1(WT). Finally, I will determine if CRms are able to alleviate any of the phenotypes induced by overexpression of PS-1(SV). This research is an essential step in identifying new and relatively simple strategies to combat aging and help treat devastating disease.