Laboratory of Aging and Neurodegeneration
The Rebeck Lab studies 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: APOE3, which is the most common form of APOE; APOE2, which lowers the risk of Alzheimer’s disease by 50%; and APOE4, which 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 brain structure, biochemistry, and behavior. 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. Using the APOE knock-in mouse model, we are also examining how the adverse effects of APOE genotype interact with the adverse effects of metabolic disturbance (obesity, diabetes) and of cancer chemotherapy (cancer chemotherapy-induced cognitive impairment).
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 prior to the onset of clinical signs.