G. William (Bill) Rebeck

Ph.D., 1991, Harvard University (Toxicology)

New Research Building, Room WP-13
Phone: 202.687.1534
Fax: 202.687.0617
E-mail: gwr2@georgetown.edu


We study the molecular mechanisms of Alzheimer's disease using a variety of approaches, including animal models, biochemistry, immunohistochemistry, and cell biology. We focus on the strongest genetic risk factor for Alzheimer’s disease: APOE. This gene encodes a protein involved in cholesterol transport and cellular repair. There are three common alleles of APOE: APOE2, APOE3, and APOE4. APOE3 is the most common form; APOE2 (present in about 10% of the US population) lowers the risk of Alzheimer’s disease by 50%; and APOE4 (present in about 25% of the US population) increases the risk by 300%. We are exploring the roles of APOE in the normal regulation of cholesterol metabolism and inflammation in the central nervous system. For this work, we are examining neurons and glia in culture, to look at normal regulation and metabolism of APOE.  We are examining the structure of the APOE protein, and its post-translational modifications and association with brain lipoproteins. We are examining mouse models in which the mouse APOE was replaced by the human forms of APOE, studying their sensitivity to brain insults, including exposure to chemotherapeutic agents. In these various studies, we are interested in the pharmacologic rescue of the effects of APOE4, particularly focusing on drugs that affect cholesterol metabolism or reduce inflammation. Finally, we are collaborating to examine the effects of APOE genotype on normal behavior and brain activity in young humans. Our goals are to understand why APOE affects the risk of Alzheimer’s disease so strongly, and to define what can be done to lower one’s risk.