Project 3: Role of Microglial ?7nAChR in Diet Induced Brain Inflammation

α7 nachr已成为治疗许多神经退行性疾病的潜在靶点。

The α7 nAChRs has emerged as a potential target in the treatment of many neurodegenerative disorders, which have been found to be associated with an inflammatory response. The α7 nAChRs are expressed in macrophages where they play a key role in the cholinergic anti-inflammatory pathway, were they have proven to be an effective target in the treatment of sepsis, myocardial ischemia, and rheumatoid arthritis. However little is known about the role that α7 nAChRs play on brain inflammation. Interestingly, it has been shown that a high fat diet on wild-type mice causes the activation of microglia resulting in impairments on working memory and in humans an elevated serum cholesterol is a risk factor for mild cognitive impairment and dementia. Suggesting that dietary fat content affects the function of the brain. Using electrophysiology and pharmacological manipulation of lipids, we demonstrated that changes in lipid levels in the plasma membrane causes dramatic changes in the function of the α7 nAChRs. To dissect the role that α7 nAChR plays on the high fat diet mediated microglia activation and subsequent development of neuroinflammation, we will generate microglia specific α7 nAChR knockout mice and compare them with control, fed either a normal or high fat diet. We will look at the activation of inflammatory responses over time, the function of neuronal α7 nAChRs, and the susceptibility of neuronal cell death caused by dietary induced changes in inflammatory response. The results will help us discern the role of α7nAChR in both microglia activation and subsequent neuronal cell death, and shed light in the possibility of targeting α7 nAChRs therapeutically in the prevention of obesity induced dementia.