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 Trushina, Roberta Diaz Brinton, Lauren P Klosinski, Jia Yao, Fei Yin, Alfred N Fonteh, Michael G Harrington, Trace A Christensen, Eugenia Trushina, Roberta Diaz Brinton
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.
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.
Figures
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![Fig. 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4703712/bin/gr6.jpg)
Fig. 7
Electron microscopic analysis of the…
Fig. 7
Electron microscopic analysis of the structural integrity of white matter in reproductively aging…
Fig. 8
Electron microscopic analysis of lipid…
Fig. 8
Electron microscopic analysis of lipid droplet accumulation in reproductively aging female mice: representative…
Fig. 9
Lipid profile of female brain…
Fig. 9
Lipid profile of female brain during reproductive aging: A. Sequence of catabolic events…
Fig. 10
Expression of proteins involved in…
Fig. 10
Expression of proteins involved in fatty acid transport and metabolism in the aging…
Fig. 11
Hippocampal, cortical and plasma ketone…
Fig. 11
Hippocampal, cortical and plasma ketone body levels in the aging female mouse: A.…
Fig. 12
Schematic model of mitochondrial H…
Fig. 12
Schematic model of mitochondrial H 2 O 2 activation of cPLA 2 -sphingomyelinase…
- Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. Ding F, et al. PLoS One. 2013 Nov 11;8(11):e79977. doi: 10.1371/journal.pone.0079977. eCollection 2013. PLoS One. 2013. PMID: 24244584 Free PMC article.
- Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence.Yao J, Hamilton RT, Cadenas E, Brinton RD. Yao J, et al. Biochim Biophys Acta. 2010 Oct;1800(10):1121-6. doi: 10.1016/j.bbagen.2010.06.002. Epub 2010 Jun 9. Biochim Biophys Acta. 2010. PMID: 20538040 Free PMC article.
- Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Yao J, et al. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5. doi: 10.1073/pnas.0903563106. Epub 2009 Aug 10. Proc Natl Acad Sci U S A. 2009. PMID: 19667196 Free PMC article.
- Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies.Chen Z, Zhong C. Chen Z, et al. Prog Neurobiol. 2013 Sep;108:21-43. doi: 10.1016/j.pneurobio.2013.06.004. Epub 2013 Jul 11. Prog Neurobiol. 2013. PMID: 23850509 Review.
- Oligomeric amyloid-beta induces MAPK-mediated activation of brain cytosolic and calcium-independent phospholipase A2 in a spatial-specific manner.Palavicini JP, Wang C, Chen L, Hosang K, Wang J, Tomiyama T, Mori H, Han X. Palavicini JP, et al. Acta Neuropathol Commun. 2017 Jul 27;5(1):56. doi: 10.1186/s40478-017-0460-6. Acta Neuropathol Commun. 2017. PMID: 28750656 Free PMC article.
- Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy.Maszka P, Kwasniak-Butowska M, Cysewski D, Slawek J, Smolenski RT, Tomczyk M. Maszka P, et al. Metabolites. 2023 Mar 1;13(3):369. doi: 10.3390/metabo13030369. Metabolites. 2023. PMID: 36984809 Free PMC article. Review.
- Alzheimer's Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity.Cerasuolo M, Papa M, Colangelo AM, Rizzo MR. Cerasuolo M, et al. Biomedicines. 2023 Mar 11;11(3):861. doi: 10.3390/biomedicines11030861. Biomedicines. 2023. PMID: 36979840 Free PMC article. Review.
- Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load.Jett S, Dyke JP, Andy C, Schelbaum E, Jang G, Boneu Yepez C, Pahlajani S, Diaz I, Diaz Brinton R, Mosconi L. Jett S, et al. Sci Rep. 2022 Dec 21;12(1):22087. doi: 10.1038/s41598-022-26573-5. Sci Rep. 2022. PMID: 36543814 Free PMC article.
- Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics.Branigan GL, Torrandell-Haro G, Vitali F, Brinton RD, Rodgers K. Branigan GL, et al. Heliyon. 2022 Oct 22;8(10):e11196. doi: 10.1016/j.heliyon.2022.e11196. eCollection 2022 Oct. Heliyon. 2022. PMID: 36325137 Free PMC article.
- Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.Eissman JM, Dumitrescu L, Mahoney ER, Smith AN, Mukherjee S, Lee ML, Scollard P, Choi SE, Bush WS, Engelman CD, Lu Q, Fardo DW, Trittschuh EH, Mez J, Kaczorowski CC, Hernandez Saucedo H, Widaman KF, Buckley RF, Properzi MJ, Mormino EC, Yang HS, Harrison TM, Hedden T, Nho K, Andrews SJ, Tommet D, Hadad N, Sanders RE, Ruderfer DM, Gifford KA, Zhong X, Raghavan NS, Vardarajan BN; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); A4 Study Team; Pericak-Vance MA, Farrer LA, Wang LS, Cruchaga C, Schellenberg GD, Cox NJ, Haines JL, Keene CD, Saykin AJ, Larson EB, Sperling RA, Mayeux R, Cuccaro ML, Bennett DA, Schneider JA, Crane PK, Jefferson AL, Hohman TJ. Eissman JM, et al. Brain. 2022 Jul 29;145(7):2541-2554. doi: 10.1093/brain/awac177. Brain. 2022. PMID: 35552371 Free PMC article.
-
- Alzheimer's A. 2015 Alzheimer's disease facts and figures. Alzheimers Dement. 2015;11:332–384. - PubMed
-
- Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol. Aging. 2004;25:5–18. (author reply 49-62) - PubMed
-
- Bartzokis G., Lu P.H., Geschwind D.H., Edwards N., Mintz J., Cummings J.L. Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch. Gen. Psychiatry. 2006;63:63–72. - PubMed
-
- Baumann N., Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev. 2001;81:871–927. - PubMed
-
- Beal M.F. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. 2005;58:495–505. - PubMed
- Research Support, N.I.H., Extramural
- Aging / genetics
- Aging / metabolism
- Alzheimer Disease / genetics
- Alzheimer Disease / metabolism*
- Animals
- Astrocytes / metabolism
- Brain / metabolism
- Cluster Analysis
- Disease Models, Animal
- Energy Metabolism
- Fatty Acids / metabolism
- Female
- Gene Expression Profiling
- Group IV Phospholipases A2 / metabolism
- Hydrogen Peroxide / metabolism
- Ketone Bodies / metabolism*
- Lipid Metabolism*
- Metabolic Networks and Pathways
- Metabolomics / methods
- Mice
- Mitochondria / metabolism
- Myelin Sheath / genetics
- Myelin Sheath / metabolism
- Neurons / metabolism
- Oxidative Stress
- Rats
- Sex Factors
- White Matter / metabolism*
- White Matter / ultrastructure
- Fatty Acids
- Ketone Bodies
- Hydrogen Peroxide
- Group IV Phospholipases A2
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Fig. 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4703712/bin/gr7.jpg)
Fig. 8
Electron microscopic analysis of lipid…
Fig. 8
Electron microscopic analysis of lipid droplet accumulation in reproductively aging female mice: representative…
Fig. 9
Lipid profile of female brain…
Fig. 9
Lipid profile of female brain during reproductive aging: A. Sequence of catabolic events…
Fig. 10
Expression of proteins involved in…
Fig. 10
Expression of proteins involved in fatty acid transport and metabolism in the aging…
Fig. 11
Hippocampal, cortical and plasma ketone…
Fig. 11
Hippocampal, cortical and plasma ketone body levels in the aging female mouse: A.…
Fig. 12
Schematic model of mitochondrial H…
Fig. 12
Schematic model of mitochondrial H 2 O 2 activation of cPLA 2 -sphingomyelinase…
- Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. Ding F, et al. PLoS One. 2013 Nov 11;8(11):e79977. doi: 10.1371/journal.pone.0079977. eCollection 2013. PLoS One. 2013. PMID: 24244584 Free PMC article.
- Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence.Yao J, Hamilton RT, Cadenas E, Brinton RD. Yao J, et al. Biochim Biophys Acta. 2010 Oct;1800(10):1121-6. doi: 10.1016/j.bbagen.2010.06.002. Epub 2010 Jun 9. Biochim Biophys Acta. 2010. PMID: 20538040 Free PMC article.
- Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Yao J, et al. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5. doi: 10.1073/pnas.0903563106. Epub 2009 Aug 10. Proc Natl Acad Sci U S A. 2009. PMID: 19667196 Free PMC article.
- Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies.Chen Z, Zhong C. Chen Z, et al. Prog Neurobiol. 2013 Sep;108:21-43. doi: 10.1016/j.pneurobio.2013.06.004. Epub 2013 Jul 11. Prog Neurobiol. 2013. PMID: 23850509 Review.
- Oligomeric amyloid-beta induces MAPK-mediated activation of brain cytosolic and calcium-independent phospholipase A2 in a spatial-specific manner.Palavicini JP, Wang C, Chen L, Hosang K, Wang J, Tomiyama T, Mori H, Han X. Palavicini JP, et al. Acta Neuropathol Commun. 2017 Jul 27;5(1):56. doi: 10.1186/s40478-017-0460-6. Acta Neuropathol Commun. 2017. PMID: 28750656 Free PMC article.
- Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy.Maszka P, Kwasniak-Butowska M, Cysewski D, Slawek J, Smolenski RT, Tomczyk M. Maszka P, et al. Metabolites. 2023 Mar 1;13(3):369. doi: 10.3390/metabo13030369. Metabolites. 2023. PMID: 36984809 Free PMC article. Review.
- Alzheimer's Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity.Cerasuolo M, Papa M, Colangelo AM, Rizzo MR. Cerasuolo M, et al. Biomedicines. 2023 Mar 11;11(3):861. doi: 10.3390/biomedicines11030861. Biomedicines. 2023. PMID: 36979840 Free PMC article. Review.
- Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load.Jett S, Dyke JP, Andy C, Schelbaum E, Jang G, Boneu Yepez C, Pahlajani S, Diaz I, Diaz Brinton R, Mosconi L. Jett S, et al. Sci Rep. 2022 Dec 21;12(1):22087. doi: 10.1038/s41598-022-26573-5. Sci Rep. 2022. PMID: 36543814 Free PMC article.
- Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics.Branigan GL, Torrandell-Haro G, Vitali F, Brinton RD, Rodgers K. Branigan GL, et al. Heliyon. 2022 Oct 22;8(10):e11196. doi: 10.1016/j.heliyon.2022.e11196. eCollection 2022 Oct. Heliyon. 2022. PMID: 36325137 Free PMC article.
- Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.Eissman JM, Dumitrescu L, Mahoney ER, Smith AN, Mukherjee S, Lee ML, Scollard P, Choi SE, Bush WS, Engelman CD, Lu Q, Fardo DW, Trittschuh EH, Mez J, Kaczorowski CC, Hernandez Saucedo H, Widaman KF, Buckley RF, Properzi MJ, Mormino EC, Yang HS, Harrison TM, Hedden T, Nho K, Andrews SJ, Tommet D, Hadad N, Sanders RE, Ruderfer DM, Gifford KA, Zhong X, Raghavan NS, Vardarajan BN; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); A4 Study Team; Pericak-Vance MA, Farrer LA, Wang LS, Cruchaga C, Schellenberg GD, Cox NJ, Haines JL, Keene CD, Saykin AJ, Larson EB, Sperling RA, Mayeux R, Cuccaro ML, Bennett DA, Schneider JA, Crane PK, Jefferson AL, Hohman TJ. Eissman JM, et al. Brain. 2022 Jul 29;145(7):2541-2554. doi: 10.1093/brain/awac177. Brain. 2022. PMID: 35552371 Free PMC article.
-
- Alzheimer's A. 2015 Alzheimer's disease facts and figures. Alzheimers Dement. 2015;11:332–384. - PubMed
-
- Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol. Aging. 2004;25:5–18. (author reply 49-62) - PubMed
-
- Bartzokis G., Lu P.H., Geschwind D.H., Edwards N., Mintz J., Cummings J.L. Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch. Gen. Psychiatry. 2006;63:63–72. - PubMed
-
- Baumann N., Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev. 2001;81:871–927. - PubMed
-
- Beal M.F. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. 2005;58:495–505. - PubMed
- Research Support, N.I.H., Extramural
- Aging / genetics
- Aging / metabolism
- Alzheimer Disease / genetics
- Alzheimer Disease / metabolism*
- Animals
- Astrocytes / metabolism
- Brain / metabolism
- Cluster Analysis
- Disease Models, Animal
- Energy Metabolism
- Fatty Acids / metabolism
- Female
- Gene Expression Profiling
- Group IV Phospholipases A2 / metabolism
- Hydrogen Peroxide / metabolism
- Ketone Bodies / metabolism*
- Lipid Metabolism*
- Metabolic Networks and Pathways
- Metabolomics / methods
- Mice
- Mitochondria / metabolism
- Myelin Sheath / genetics
- Myelin Sheath / metabolism
- Neurons / metabolism
- Oxidative Stress
- Rats
- Sex Factors
- White Matter / metabolism*
- White Matter / ultrastructure
- Fatty Acids
- Ketone Bodies
- Hydrogen Peroxide
- Group IV Phospholipases A2
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Fig. 8](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4703712/bin/gr8.jpg)
Fig. 9
Lipid profile of female brain…
Fig. 9
Lipid profile of female brain during reproductive aging: A. Sequence of catabolic events…
Fig. 10
Expression of proteins involved in…
Fig. 10
Expression of proteins involved in fatty acid transport and metabolism in the aging…
Fig. 11
Hippocampal, cortical and plasma ketone…
Fig. 11
Hippocampal, cortical and plasma ketone body levels in the aging female mouse: A.…
Fig. 12
Schematic model of mitochondrial H…
Fig. 12
Schematic model of mitochondrial H 2 O 2 activation of cPLA 2 -sphingomyelinase…
- Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. Ding F, et al. PLoS One. 2013 Nov 11;8(11):e79977. doi: 10.1371/journal.pone.0079977. eCollection 2013. PLoS One. 2013. PMID: 24244584 Free PMC article.
- Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence.Yao J, Hamilton RT, Cadenas E, Brinton RD. Yao J, et al. Biochim Biophys Acta. 2010 Oct;1800(10):1121-6. doi: 10.1016/j.bbagen.2010.06.002. Epub 2010 Jun 9. Biochim Biophys Acta. 2010. PMID: 20538040 Free PMC article.
- Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Yao J, et al. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5. doi: 10.1073/pnas.0903563106. Epub 2009 Aug 10. Proc Natl Acad Sci U S A. 2009. PMID: 19667196 Free PMC article.
- Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies.Chen Z, Zhong C. Chen Z, et al. Prog Neurobiol. 2013 Sep;108:21-43. doi: 10.1016/j.pneurobio.2013.06.004. Epub 2013 Jul 11. Prog Neurobiol. 2013. PMID: 23850509 Review.
- Oligomeric amyloid-beta induces MAPK-mediated activation of brain cytosolic and calcium-independent phospholipase A2 in a spatial-specific manner.Palavicini JP, Wang C, Chen L, Hosang K, Wang J, Tomiyama T, Mori H, Han X. Palavicini JP, et al. Acta Neuropathol Commun. 2017 Jul 27;5(1):56. doi: 10.1186/s40478-017-0460-6. Acta Neuropathol Commun. 2017. PMID: 28750656 Free PMC article.
- Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy.Maszka P, Kwasniak-Butowska M, Cysewski D, Slawek J, Smolenski RT, Tomczyk M. Maszka P, et al. Metabolites. 2023 Mar 1;13(3):369. doi: 10.3390/metabo13030369. Metabolites. 2023. PMID: 36984809 Free PMC article. Review.
- Alzheimer's Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity.Cerasuolo M, Papa M, Colangelo AM, Rizzo MR. Cerasuolo M, et al. Biomedicines. 2023 Mar 11;11(3):861. doi: 10.3390/biomedicines11030861. Biomedicines. 2023. PMID: 36979840 Free PMC article. Review.
- Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load.Jett S, Dyke JP, Andy C, Schelbaum E, Jang G, Boneu Yepez C, Pahlajani S, Diaz I, Diaz Brinton R, Mosconi L. Jett S, et al. Sci Rep. 2022 Dec 21;12(1):22087. doi: 10.1038/s41598-022-26573-5. Sci Rep. 2022. PMID: 36543814 Free PMC article.
- Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics.Branigan GL, Torrandell-Haro G, Vitali F, Brinton RD, Rodgers K. Branigan GL, et al. Heliyon. 2022 Oct 22;8(10):e11196. doi: 10.1016/j.heliyon.2022.e11196. eCollection 2022 Oct. Heliyon. 2022. PMID: 36325137 Free PMC article.
- Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.Eissman JM, Dumitrescu L, Mahoney ER, Smith AN, Mukherjee S, Lee ML, Scollard P, Choi SE, Bush WS, Engelman CD, Lu Q, Fardo DW, Trittschuh EH, Mez J, Kaczorowski CC, Hernandez Saucedo H, Widaman KF, Buckley RF, Properzi MJ, Mormino EC, Yang HS, Harrison TM, Hedden T, Nho K, Andrews SJ, Tommet D, Hadad N, Sanders RE, Ruderfer DM, Gifford KA, Zhong X, Raghavan NS, Vardarajan BN; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); A4 Study Team; Pericak-Vance MA, Farrer LA, Wang LS, Cruchaga C, Schellenberg GD, Cox NJ, Haines JL, Keene CD, Saykin AJ, Larson EB, Sperling RA, Mayeux R, Cuccaro ML, Bennett DA, Schneider JA, Crane PK, Jefferson AL, Hohman TJ. Eissman JM, et al. Brain. 2022 Jul 29;145(7):2541-2554. doi: 10.1093/brain/awac177. Brain. 2022. PMID: 35552371 Free PMC article.
-
- Alzheimer's A. 2015 Alzheimer's disease facts and figures. Alzheimers Dement. 2015;11:332–384. - PubMed
-
- Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol. Aging. 2004;25:5–18. (author reply 49-62) - PubMed
-
- Bartzokis G., Lu P.H., Geschwind D.H., Edwards N., Mintz J., Cummings J.L. Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch. Gen. Psychiatry. 2006;63:63–72. - PubMed
-
- Baumann N., Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev. 2001;81:871–927. - PubMed
-
- Beal M.F. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. 2005;58:495–505. - PubMed
- Research Support, N.I.H., Extramural
- Aging / genetics
- Aging / metabolism
- Alzheimer Disease / genetics
- Alzheimer Disease / metabolism*
- Animals
- Astrocytes / metabolism
- Brain / metabolism
- Cluster Analysis
- Disease Models, Animal
- Energy Metabolism
- Fatty Acids / metabolism
- Female
- Gene Expression Profiling
- Group IV Phospholipases A2 / metabolism
- Hydrogen Peroxide / metabolism
- Ketone Bodies / metabolism*
- Lipid Metabolism*
- Metabolic Networks and Pathways
- Metabolomics / methods
- Mice
- Mitochondria / metabolism
- Myelin Sheath / genetics
- Myelin Sheath / metabolism
- Neurons / metabolism
- Oxidative Stress
- Rats
- Sex Factors
- White Matter / metabolism*
- White Matter / ultrastructure
- Fatty Acids
- Ketone Bodies
- Hydrogen Peroxide
- Group IV Phospholipases A2
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Fig. 9](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4703712/bin/gr9.jpg)
![Fig. 10](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4703712/bin/gr10.jpg)
Fig. 11
Hippocampal, cortical and plasma ketone…
Fig. 11
Hippocampal, cortical and plasma ketone body levels in the aging female mouse: A.…
Fig. 12
Schematic model of mitochondrial H…
Fig. 12
Schematic model of mitochondrial H 2 O 2 activation of cPLA 2 -sphingomyelinase…
- Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. Ding F, et al. PLoS One. 2013 Nov 11;8(11):e79977. doi: 10.1371/journal.pone.0079977. eCollection 2013. PLoS One. 2013. PMID: 24244584 Free PMC article.
- Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence.Yao J, Hamilton RT, Cadenas E, Brinton RD. Yao J, et al. Biochim Biophys Acta. 2010 Oct;1800(10):1121-6. doi: 10.1016/j.bbagen.2010.06.002. Epub 2010 Jun 9. Biochim Biophys Acta. 2010. PMID: 20538040 Free PMC article.
- Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease.Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Yao J, et al. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5. doi: 10.1073/pnas.0903563106. Epub 2009 Aug 10. Proc Natl Acad Sci U S A. 2009. PMID: 19667196 Free PMC article.
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- Alzheimer's A. 2015 Alzheimer's disease facts and figures. Alzheimers Dement. 2015;11:332–384. - PubMed
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- Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol. Aging. 2004;25:5–18. (author reply 49-62) - PubMed
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- Bartzokis G., Lu P.H., Geschwind D.H., Edwards N., Mintz J., Cummings J.L. Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch. Gen. Psychiatry. 2006;63:63–72. - PubMed
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- Baumann N., Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev. 2001;81:871–927. - PubMed
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- Beal M.F. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. 2005;58:495–505. - PubMed
- Research Support, N.I.H., Extramural
- Aging / genetics
- Aging / metabolism
- Alzheimer Disease / genetics
- Alzheimer Disease / metabolism*
- Animals
- Astrocytes / metabolism
- Brain / metabolism
- Cluster Analysis
- Disease Models, Animal
- Energy Metabolism
- Fatty Acids / metabolism
- Female
- Gene Expression Profiling
- Group IV Phospholipases A2 / metabolism
- Hydrogen Peroxide / metabolism
- Ketone Bodies / metabolism*
- Lipid Metabolism*
- Metabolic Networks and Pathways
- Metabolomics / methods
- Mice
- Mitochondria / metabolism
- Myelin Sheath / genetics
- Myelin Sheath / metabolism
- Neurons / metabolism
- Oxidative Stress
- Rats
- Sex Factors
- White Matter / metabolism*
- White Matter / ultrastructure
- Fatty Acids
- Ketone Bodies
- Hydrogen Peroxide
- Group IV Phospholipases A2
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
![Fig. 11](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4703712/bin/gr11.jpg)
Fig. 12
Schematic model of mitochondrial H…
Fig. 12
Schematic model of mitochondrial H 2 O 2 activation of cPLA 2 -sphingomyelinase…
![Fig. 12](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4703712/bin/gr12.jpg)
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Source: PubMed