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2011 Grants - Landreth
Mechanisms of RXR-Stimulated Reversal of Amyloid-Induced Phenotypes
Gary Landreth, Ph.D.
Case Western Reserve University
2011 Zenith Fellows Award
Retinoid X receptor (RXR) is a protein in cells that controls the expression of other proteins by regulating cellular genes. One of the genes regulated by RXR is the ApoE gene. This regulation is important because defects in the ApoE protein are known to be a strong risk factor for Alzheimer's disease; thus, regulation of ApoE expression may also influence the risk for disease.
Gary Landreth, Ph.D., and colleagues have been studying how activation of RXR affects the development of Alzheimer's-like pathology. For these studies, they use mice that have been genetically altered to express high levels of beta-amyloid, a protein fragment that aggregates to form amyloid plaques, one of the hallmarks of Alzheimer's pathology. Dr. Landreth's research team found that bexarotene, a drug that activates RXR, rapidly reduces brain beta-amyloid levels in mice when given orally. After treatment, the mice also exhibit improvements in learning and memory. The researchers have proposed to study how bexarotene improves clearance of beta-amyloid from the brain, focusing on the role of ApoE because this protein is known to be involved in this process. They also plan to study how other cells in the brain, known as microglia and phagocytes, participate in the clearance of beta-amyloid. These studies will advance knowledge of how beta-amyloid is cleared from the brain and whether activation of the RXR protein may be a potential target for drugs to treat Alzheimer's disease.