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2017 Grants - Pike
Interactions Between Sex, APOE4, and Neuroinflammation in Alzheimer's Disease Pathogenesis
Christian J. Pike, Ph.D.
University of Southern California
Los Angeles, California
2017 Sex and Gender in Alzheimer’s (SAGA) Grant
Do natural variations in the APOE gene impact brain inflammation and risk for Alzheimer’s differently in males and females?
Apolipoprotein E (APOE) is a gene that is found in three different variations; APOE -e2, e3 and e4. The APOE-e4 variant is a genetic risk factor for Alzheimer’s disease in both men and woman but appears to disproportionately increase the risk in women. The higher risk associated with APOE-e4 in women compared to men suggests that a person’s sex interacts with the type of APOE gene they carry. However, scientists do not understand this interaction and the mechanisms that may underlie it. One possibility is that the hormone estrogen, found at much higher levels in women than men, influences how APOE-e4 affects the brain. APOE-e4 and the sex steroid hormones (such as estrogen) have been shown to affect brain inflammation (neuroinflammation), which is a characteristic feature of Alzheimer’s disease.
Christopher J. Pike, Ph.D., and colleagues have proposed a series of experiments in mice to explore how the APOE gene and sex interact to influence the development of Alzheimer’s-like changes in the brain. Using mice genetically altered to have different versions of the human APOE gene, Dr. Pike’s team will study whether the APOE-e4 version is associated with higher levels of brain inflammation and memory problems in female mice when compared to male mice. In another series of experiments, the researchers will control the degree of “maleness” or “femaleness” in the brain as the mice develop and determine if this changes how APOE-e4 contributes to Alzheimer’s-like features in the mice. Finally, Dr. Pike and colleagues will study whether two different anti-inflammatory drugs can reduce the effects of the APOE-e4 on neuroinflammation and other Alzheimer’s-like brain changes.
These studies could advance our understanding of the relationships between APOE, neuroinflammation and Alzheimer’s in both males and females. Clarifying these complex mechanisms could inform the development of new treatments to slow or prevent Alzheimer’s disease in both sexes.