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2012 Grants - Fitz
Effect of RXR Agonist on Alzheimer's Phenotype In APP Mice Expressing APOE-e3 and e4
Nicholas Fitz, Ph.D.
University of Pittsburgh
2012 New Investigator Research Grant
Apolipoprotein-E (APOE) is a brain protein that normally is thought to play an important role in transporting lipids (fats) into cells. The genes that produce this protein occur in several forms. One of the forms, known as APOE-e4, has been shown to increase a person's risk for developing Alzheimer's disease. Yet scientists do not know exactly why this association between APOE-e4 and Alzheimer's risk exists.
In preliminary research, Nicholas Fitz, Ph.D., and colleagues have found that mice with the e4 variant produce less APOE protein than do mice with the more benign APOE-e3 gene variant. Moreover, the e4 mice also produce greater than normal levels of toxic beta-amyloid, a protein fragment that is a key suspect in Alzheimer's. These findings support the hypothesis that APOE protein inhibits beta-amyloid production, and that the e4 gene promotes beta-amyloid activity by failing to generate sufficient amounts of its own protein.
For their current study, Dr. Fitz and colleagues will expand their earlier research by studying the effect of a drug called bexarotene. This drug will be administered to mice that have either the APOE-e4 gene or the APOE-e3 gene. Bexarotene activates a protein called the retinoid X receptor (RXR), which can help boost the expression of APOE protein. The researchers will then compare how their bexarotene treatment affects brain beta-amyloid levels and cognition in their mice. If the treatment is able to ameliorate Alzheimer's symptoms in the e4 mice, this result could confirm the role of APOE protein in fighting dementia. It could also identify RXR as novel therapeutic target for Alzheimer's.