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

Lauren P. Klosinski, Jia Yao, Fei Yin, Alfred N. Fonteh, Michael G. Harrington, Trace A. Christensen, Eugenia D Trushina, Roberta Diaz Brinton

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1888-1904
Number of pages17
JournalEBioMedicine
Volume2
Issue number12
DOIs
StatePublished - Dec 1 2015

Fingerprint

Ketone Bodies
Brain
Alzheimer Disease
Aging of materials
Lipids
Myelin Sheath
Fatty Acids
Chemical activation
Cytosolic Phospholipases A2
Neurodegenerative diseases
Sphingomyelin Phosphodiesterase
Demyelinating Diseases
Metabolism
Neurodegenerative Diseases
Hydrogen Peroxide
Multiple Sclerosis
Machinery
Respiration
Animals
Animal Models

Keywords

  • Aging oxidative stress
  • Alzheimer's disease
  • Cytosolic phospholipase A2
  • Ketone bodies
  • Mitochondria
  • Neurodegeneration
  • White matter

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Klosinski, L. P., Yao, J., Yin, F., Fonteh, A. N., Harrington, M. G., Christensen, T. A., ... Brinton, R. D. (2015). White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease. EBioMedicine, 2(12), 1888-1904. https://doi.org/10.1016/j.ebiom.2015.11.002

White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain : Implications for Alzheimer's Disease. / Klosinski, Lauren P.; Yao, Jia; Yin, Fei; Fonteh, Alfred N.; Harrington, Michael G.; Christensen, Trace A.; Trushina, Eugenia D; Brinton, Roberta Diaz.

In: EBioMedicine, Vol. 2, No. 12, 01.12.2015, p. 1888-1904.

Research output: Contribution to journalArticle

Klosinski, LP, Yao, J, Yin, F, Fonteh, AN, Harrington, MG, Christensen, TA, Trushina, ED & Brinton, RD 2015, 'White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease', EBioMedicine, vol. 2, no. 12, pp. 1888-1904. https://doi.org/10.1016/j.ebiom.2015.11.002
Klosinski LP, Yao J, Yin F, Fonteh AN, Harrington MG, Christensen TA et al. White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease. EBioMedicine. 2015 Dec 1;2(12):1888-1904. https://doi.org/10.1016/j.ebiom.2015.11.002
Klosinski, Lauren P. ; Yao, Jia ; Yin, Fei ; Fonteh, Alfred N. ; Harrington, Michael G. ; Christensen, Trace A. ; Trushina, Eugenia D ; Brinton, Roberta Diaz. / White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain : Implications for Alzheimer's Disease. In: EBioMedicine. 2015 ; Vol. 2, No. 12. pp. 1888-1904.
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