N-3 Polyunsaturated Fatty Acids and Neuroinflammation in Alzheimer's Disease

Neuroinflammation may factor in the etiology of Alzheimer’s Disease (AD). n-3 polyunsaturated fatty acids (PUFA) and their bioactive lipid mediator derivatives have inflammation-modulating properties. Epidemiological and animal data suggests n-3 PUFA may be protective in AD, but whether this protection is conferred by modulating neuroinflammation is unknown. To determine how integral neuroinflammation is to AD pathology, a systematic review was conducted of studies comparing microglial markers in post-mortem human brain samples from patients with AD and controls. The analysis of 114 studies presented in Chapter 2 showed that markers of microglial activation are elevated in AD, suggesting that neuroinflammation is an important feature of the disease. A series of experiments were conducted to examine the effects of n-3 PUFA on neuroinflammation in an AD model. Fat-1 transgenic mice, animals that endogenously synthesize n-3 PUFA, and their wildtype littermates were fed either a n-3 PUFA deprived safflower oil diet, or a fish oil diet containing n-3 PUFA. In Chapter 3, we examined the time-course of neuroinflammation and its resolution following intracerebroventricular infusion of amyloid-β 1-40. Wildtype mice fed the n-3 PUFA-deprived diet exhibited a greater increase in microglia proliferation, more neuronal death, and alterations in microglia morphology consistent with activation, with no changes in the time-course of resolution. In Chapter 4, we show that fish oil-fed mice have a greater astrocyte activation response to amyloid-β than either the safflower-fed or fat-1 animals. Using a microarray in Chapter 5, we found that safflower oil-fed mice exhibited greater enrichment of gene categories associated with inflammation than fish oil-fed mice, independent of changes in levels of lipid mediators. Together, the data in this thesis show that neuroinflammation is a common pathological feature of AD that is modulated by brain n-3 PUFA. This does not seem to require detectable changes in bioactive lipid mediators.Ph.D.2018-06-19 00:00:0