The apolipoprotein E gene isotype E4 (apoE4) is a common and strong genetic risk factor for developing Alzheimer's disease (AD), leading to an earlier age of onset of all AD phenotypes. The mechanisms by which it does so remain elusive, but may involve inflammation and dysregulation of the innate immune system. A key component of the innate immune system is the microRNA miR146a which feedback controls inflammatory responses upon transcriptional upregulation of its expression. We have discovered that the expression of miR146a in the brain of young transgenic mice that express apoE4 is greatly reduced compared to levels in apoE3 mice. This could prevent miR146a from feedback regulating inflammatory responses leading to chronic inflammation that is observed generally with apoE4 and in AD. The transcriptional regulation of miR146a is, like many genes, modulated by epigenetic modifications of the gene's associated histones. The inflammatory regulation of miR146a has been shown to become dysfunctional with age by changes in this epigenetic modifications at the miR146a transcription promoter. Importantly, apoE4 causes changes in histone modification that is similar to that which occurs with aging at the miR146a promoter. Therefore, apoE4 may exert its effect on miR146a by changing the histone modifications at the miR146a promoter leading to downregulation of its expression. This hypothesis is tested in this proposal, measuring these epigenetic modifications at the miR146a promoter in brain tissue comparing young apoE4 to young apoE3 mice. Results in mice will be validated in a human microglial cell line. To evaluate whether this effect seen in young mice is age-dependent, identified changes relevant to miR146a expression control will be measured across age (young to old) in apoE4 and apoE3 mice brain. Inflammatory effects of apoE4 are also observed systemically in the blood. We will determine if similar effects of apoE4 occur in blood, both in transgenic mice and in human blood across middle to old age. This may provide a peripheral biomarker of apoE4-induced inflammatory dysregulation, which could be used as a peripheral biomarker for monitoring the efficacy of therapeutics directed at this phenotype of apoE4. Exercise is a strong candidate cognitive therapeutic for which there is evidence that apoE4 could be particularly responsive. In response to exercise, we will measure miR146a and relevant expression control factors in transgenic mice that express, in addition of E3 or E4, familial Alzheimer's genes. These studies may lead to discovering a new mechanism for the apoE4 genetic effect in AD, and open new avenues of research, and may discover an implementable therapeutic (exercise) that could prevent the early-age onset of apoE4-dependent inflammation. This prevention could eliminate the seed of events that eventually leads to AD.
ApoE4 is a common and strong genetic risk factor for developing Alzheimer's disease, but the mechanisms by which it does so remain elusive. This proposal is based on findings in genetically altered mice, suggesting that ApoE4 contributes to a fundamental dysregulation in the immune system, which may be corrected by exercise. This study will not only help elucidate the immune mechanisms of ApoE4, but will demonstrate whether exercise in young adulthood can eliminate the increased risk in E4 carriers.
