Neural stem cells and adult brain fatty acid metabolism: Lessons from the 3xTg model of Alzheimer's disease

Abstract

Neural stem cell (NSC) activity and adult neurogenesis are physiologically relevant regulators of adult brain structure, function and repair. Given these roles, the NSC impairments observed in a wide range of neurodegenerative and psychiatric conditions likely factor into the overall cognitive dysfunction in these conditions. We investigated NSC regulation in the context of Alzheimer's disease (AD) using the well-characterised triple transgenic (3xTg) model of AD. In this review, we describe our recent findings that link 3xTg-AD neurogenesis impairments to AD-associated abnormalities in brain fatty acid metabolism. Notably, we identified an accumulation of triglycerides rich in oleic acid, a mono-unsaturated fatty acid, within the forebrain NSC niche in AD. Inhibiting the local conversion of saturated to mono-unsaturated fatty acids within the brain was sufficient to counteract the loss of NSC activity in 3xTg-AD mice (Hamilton et al., 2015). We place these findings within the context of recent evidence that dynamic changes in lipid metabolism occur during the transition from NSC quiescence to activation. The picture that emerges is that the critical NSC quiescence-to-activation decision is sensitive to the local levels of specific fatty acids and can be impaired by a disease-associated shift in brain fatty acid balance.