Sangram Sisodia PhD has focused his research on the cellular and molecular biology of the B-amyloid precursor protein (APP), or presenilins (PS1 and PS2), molecules that are mutated in autosomal dominant, familial forms of Alzheimer's disease (FAD) over the past 18 years. His work integrates genetic, neurobiologic, molecular and cellular methodologies. He has demonstrated that APP is subject to rapid anterograde transport and subject to proteolytic processing at, or near, terminal fields in the CNS. His ongoing investigations are aimed at examining regulation of APP trafficking and processing in vivo using cellular imaging and biochemical approaches that rely on introduction of recombinant lentiviral-driven APP-GFP chimeras into cultured neurons and hippocampal slices. In order to assess the function of PS, he has used gene targeting strategies; PS1-deficient animals die in late embryogenesis due to defective Notch signaling that is in large part, the result of failed intramembranous, “y-secretase” processing of a membrane-bound Notch substrate. Genetic and biochemical evidence has revealed that PS interacts with nicastrin, APH1 and PEN-2 in high molecular weight complexes, and Dr. Sisodia’s group is actively engaged in cell biological, biochemical and structural studies to understand the temporal assembly of these membrane proteins, the nature of subunit interactions and the enzymatic mechanism(s) by which the complex promotes "y-secretase" processing of Notch, APP and other type 1 membrane proteins.
A significant effort of the Sisodia laboratory has been to develop and characterize transgenic animals that express FAD-linked variants of APP and PS1 and mice with conditionally inactivated PS to clarify the underlying biochemical and pathophysiological alterations that cause AD and issues relevant to axonal trafficking of membrane proteins, neurotransmission, neuronal vulnerability, neurogenesis, gene expression and APP/AB metabolism. More recently, they have demonstrated that enriched environments and exercise modulate A? metabolism and deposition in vivo, and are investigating a gene expression profile our ongoing efforts are focused on the role of polypeptides encoded by genes that are selectively regulated in these settings.