title: White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease.
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.
authors: Department of Neuroscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA.
authors: Lauren P
authors: LP
authors: Klosinski
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors: Jia
authors: J
authors: Yao
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors: Fei
authors: F
authors: Yin
authors: Huntington Medical Research Institutes, Pasadena, CA, USA.
authors: Alfred N
authors: AN
authors: Fonteh
authors: Huntington Medical Research Institutes, Pasadena, CA, USA.
authors: Michael G
authors: MG
authors: Harrington
authors: Department of Neurology, Mayo Clinic Rochester, MN, USA.
authors: Trace A
authors: TA
authors: Christensen
authors: Department of Neurology, Mayo Clinic Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors: Eugenia
authors: E
authors: Trushina
authors: Department of Neuroscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: Roberta Diaz
authors: RD
authors: Brinton
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism*; D050356:Lipid Metabolism; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D012737:Sex Factors; D066127:White Matter / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D005227:Fatty Acids; D007657:Ketone Bodies; D006861:Hydrogen Peroxide; D054513:Group IV Phospholipases A2
keywords: ABAD, Aβ-binding alcohol dehydrogenase; ABAD, Aβ-binding-alcohol-dehydrogenase; ACER3, alkaline ceramidase; AD, Alzheimer's disease; APO-ε4, apolipoprotein ε4; APP, amyloid precursor protein; Aging oxidative stress; Alzheimer's disease; BACE1, beta-secretase 1; BBB, blood brain barrier; CC, corpus callosum; CMRglu, cerebral glucose metabolic rate; COX, complex IV cytochrome c oxidase; CPT1, carnitine palmitoyltransferase 1; Cldn11, claudin 11; Cyp2j6, arachidonic acid epoxygenase; Cytosolic phospholipase A2; DHA, docosahexaesnoic acid; Erbb3, Erb-B2 receptor tyrosine kinase 3; FDG-PET, 2-[18F]fluoro-2-deoxy-d-glucose; GFAP, glial fibrillary acidic protein; H2O2, hydrogen peroxide; HADHA, hydroxyacyl-CoA dehydrogenase; HK, hexokinase; Ketone bodies; LC MS, liquid chromatography mass spectrometer; MAG, myelin associated glycoprotein; MBP, myelin basic protein; MCT1, monocarboxylate transporter 1; MIB, mitochondrial isolation buffer; MOG, myelin oligodendrocyte glycoprotein; MTL, medial temporal lobe; Mitochondria; NEFA, nonesterified fatty acids; Neurodegeneration; OCR, oxygen consumption rate; Olig2, oligodendrocyte transcription factor; PB, phosphate buffer; PCC, posterior cingulate; PCR, polymerase chain reaction; PDH, pyruvate dehydrogenase; PEI, polyethyleneimine; RCR, respiratory control ratio; ROS, reactive oxygen species; S1P, sphingosine; TLDA, TaqMan low density array; WM, white matter; WT, wild type; White matter; cPLA2, cytosolic phospholipase A2