Neural Stem Cells and Adult Brain Fatty Acid Metabolism: Lessons from the 3xTg Model of Alzheimer's Disease
Overview
Authors
Affiliations
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.
Age-Related Neurodegenerative Diseases: A Stem Cell's Perspective.
Calvo B, Schembri-Wismayer P, Duran-Alonso M Cells. 2025; 14(5).
PMID: 40072076 PMC: 11898746. DOI: 10.3390/cells14050347.
Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders.
Loix M, Vanherle S, Turri M, Kemp S, Fernandes K, Hendriks J Mol Neurodegener. 2024; 19(1):85.
PMID: 39563397 PMC: 11575020. DOI: 10.1186/s13024-024-00778-w.
Natnan M, Low C, Chong C, Jasmany M, Baharum S Fish Physiol Biochem. 2024; 50(6):2327-2342.
PMID: 39102011 DOI: 10.1007/s10695-024-01389-4.
Causal effects of fatty acids on depression: Mendelian randomization study.
Zeng L, Lv H, Wang X, Xue R, Zhou C, Liu X Front Nutr. 2022; 9:1010476.
PMID: 36562041 PMC: 9763462. DOI: 10.3389/fnut.2022.1010476.
Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?.
Martinez-Cue C, Bartesaghi R Nutrients. 2022; 14(14).
PMID: 35889838 PMC: 9323400. DOI: 10.3390/nu14142880.