Our laboratory focuses on the molecular events underlying neurodegeneration in aging, and particularly in Alzheimer's disease (AD). Among other neuropathological features, cortical deposition of an insoluble material, called amyloid, occurs in both the aging and the AD-afflicted brain. The main component of the amyloid plaque is a small peptide, the ß-amyloid protein (Aß). We are interested in identifying the cellular pathways regulating the generation of the Aß protein, and the factors involved in the subsequent neurodegenerative process associated with this peptide.

Current areas of study include:

1. Molecular mechanisms of neurodegenerative diseases, with a focus on Alzheimer’s disease

2. The role of cholesterol in Alzheimer’s disease pathogenesis

3. Use of cholesterol-modulating agents as therapeutics for Alzheimer’s disease

4. Biological and pathological functions of the enzymes responsible for generating A ß (presenilin/ g -secretase and BACE)

5. Role of ion channel dysfunction in Alzheimer’s disease

Regarding the cholesterol-related projects, we have found that not only membrane cholesterol, but also by intracellular cholesteryl-esters regulate production of A ß . We have shown that ACAT (acyl-coenzyme A:cholesterol acyltransferase) inhibitors, designed to reduce cholesteryl-ester levels, also inhibit A ß generation in cells and AD transgenic animal models. Importantly, following administration of an ACAT inhibitor, we found that mice were almost completely free of amyloid deposits and performed better in a spatial learning and memory test. The cell-based and mouse studies resulted in separate publications in Nature Cell Biology and Neuron. The latter was featured as a lead article in Focus (HMS), numerous media articles, as well as in the News sections of Lancet Neurology. ACAT inhibitor drugs are already in clinical development, having undergone phase III clinical trials for prevention of atherosclerosis. Over the next year, we will examine whether amyloid pathology is reduced by a phase III ACAT inhibitor in a new set of transgenic animals and analyze the molecular mechanism by which ACAT inhibitors reduce A ß generation. Our overarching goal is to provide evidence that would strongly encourage clinical trial of ACAT inhibitors for AD.

Our second major project concerns the physiological function of presenilin/ g -secretase, an enzyme complex that plays a pivotal role in the generation of A ß . We have recently identified four novel substrates for presenilin-dependent proteolysis, including the ß 2-subunit of the voltage-gated sodium channel (VGSC). We are in the process of establishing a signaling pathway involving VGSC- ß 2 proteolytic fragments, which we have shown to activate transcription of VGSC a channels. These findings may explain why VGSC a channel levels and mRNA are elevated in AD brains. Other projects involve examining the role of lipids other than cholesterol, such as ceramide and sphingolipids, in A ß generation, characterization of the role of ß -secretase (BACE) cleavage in the regulation of voltage-gated sodium channel function, and the identification of cell surface chaperone proteins of APP.