Miguel Aguinaga

Early onset Alzheimer's disease is shown to be associated with mutations in genes including, presenilin 1 (PSEN1) and presenilin 2 (PSEN2). These genes encode 𝛾-secretase, which carries out proteolytic cleavages of many transmembrane proteins and mutations within 𝛾-secretase alter its activity in correlation to disease. One such transmembrane protein cleaved by 𝛾-secretase includes deleted in colorectal cancer (DCC). DCC functions as a receptor for Netrin-1 and together they regulate synaptogenesis during nervous system development; beyond development, DCC regulates plasticity in the adult brain. Consequences of its cleavage align with these ideas as receptor-mediated intracellular signaling and regulation of glutamatergic transmission becomes attenuated. Although cleavage of DCC in itself appears to disrupt proper neuronal signaling, studies have yet to examine the potential of cleaved DCC aggregation as an additional factor within molecular neurodegenerative symptomatology. This project sought to utilize mammalian cell lines in order to produce and attain the cleaved form of the two DCC isoforms. Cells transfected to express the short isoform of DCC either exhibited low expression or cell death. Cells expressing the long form had higher expression and were more able to proliferate. This demonstrated that the cleaved short isoform may indeed induce cell toxicity. Purified samples of both isoforms were successfully attained and verified. Future experiments will include treating hippocampal neurons with purified concentrations of DCC and analyzing markers of cell heath via immunocytochemistry. Markers of cell death, presynaptic and postsynaptic proteins will be compared between treated and control groups of neurons.