White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease.

TitleWhite Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease.
Publication TypeJournal Article
Year of Publication2015
AuthorsKlosinski LP, Yao J, Yin F, Fonteh AN, Harrington MG, Christensen TA, Trushina E, Brinton RDiaz
Date Published2015 Dec
KeywordsAging, Alzheimer Disease, Animals, Astrocytes, Brain, Cluster Analysis, Disease Models, Animal, Energy Metabolism, Fatty Acids, Female, Gene Expression Profiling, Group IV Phospholipases A2, Hydrogen Peroxide, Ketone Bodies, Lipid Metabolism, Metabolic Networks and Pathways, Metabolomics, Mice, Mitochondria, Myelin Sheath, Neurons, Oxidative Stress, Rats, Sex Factors, White Matter

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.

Alternate JournalEBioMedicine
PubMed ID26844268
PubMed Central IDPMC4703712
Grant ListR01 AG033288 / AG / NIA NIH HHS / United States
R01 ES020715 / ES / NIEHS NIH HHS / United States
R01AG033288 / AG / NIA NIH HHS / United States
P01AG026572 / AG / NIA NIH HHS / United States
U24 DK100469 / DK / NIDDK NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
R01ES020715 / ES / NIEHS NIH HHS / United States
P01 AG026572 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D
Fei Yin, Ph.D.