Alzheimer's Disease

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.

Gopal Thinakaran PhD (Department of Neurobiology) focuses on the cell biology of AB production. He is particularly interested in defining regulation of APP trafficking and defining subcellular sites of APP processing by BACE1 and y-secretase. His group is also interested in y-secretase processing of proteins that play important functions in the nervous system such as Notch and DCC. He uses an integrated approach that combines hypothesis driven mutagenesis, biochemical characterization, and detailed subcellular localization and live imaging strategies to dissect the regulation of AB production and intramembranous cleavage of select type I membrane protein substrates of y-secretase. Similarly, initial promising pre-therapeutic trials of inhibition of y-secretase with highly selective inhibitors were found to cause adverse effects related to mechanism based toxicity, inhibition of Notch processing. Dr. Thinikaran’s research on metabolic pathways that regulate AB production is highly relevant to therapeutic targeting of APP secretases in a manner that selectively attenuates APP processing without adversely affecting Notch cleavage. Consequently, he believes that his studies will be critical to develop novel rational Alzheimer’s disease therapeutics aimed at reducing AB burden in the brain.