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Biological sex and DNA repair deficiency drive Alzheimer’s disease via systemic metabolic remodeling and brain mitochondrial dysfunction

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Abstract

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is more prevalent in women. The increased risk of AD in women is not well understood. It is well established that there are sex differences in metabolism and that metabolic alterations are an early component of AD. We utilized a cross-species approach to evaluate conserved metabolic alterations in the serum and brain of human AD subjects, two AD mouse models, a human cell line, and two Caenorhabditis elegans AD strains. We found a mitochondrial complex I-specific impairment in cortical synaptic brain mitochondria in female, but not male, AD mice. In the hippocampus, Polβ haploinsufficiency caused synaptic complex I impairment in male and female mice, demonstrating the critical role of DNA repair in mitochondrial function. In non-synaptic, glial-enriched, mitochondria from the cortex and hippocampus, complex II-dependent respiration increased in female, but not male, AD mice. These results suggested a glial upregulation of fatty acid metabolism to compensate for neuronal glucose hypometabolism in AD. Using an unbiased metabolomics approach, we consistently observed evidence of systemic and brain metabolic remodeling with a shift from glucose to lipid metabolism in humans with AD, and in AD mice. We determined that this metabolic shift is necessary for cellular and organismal survival in C. elegans, and human cell culture AD models. We observed sex-specific, systemic, and brain metabolic alterations in humans with AD, and that these metabolite changes significantly correlate with amyloid and tau pathology. Among the most significant metabolite changes was the accumulation of glucose-6-phosphate in AD, an inhibitor of hexokinase and rate-limiting metabolite for the pentose phosphate pathway (PPP). Overall, we identified novel mechanisms of glycolysis inhibition, PPP, and tricarboxylic acid cycle impairment, and a neuroprotective augmentation of lipid metabolism in AD. These findings support a sex-targeted metabolism-modifying strategy to prevent and treat AD.

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References

  1. Adami PVM, Quijano C, Magnani N, Galeano P, Evelson P, Cassina A et al (2017) Synaptosomal bioenergetic defects are associated with cognitive impairment in a transgenic rat model of early Alzheimer’s disease. J Cereb Blood Flow Metab 37:69–84. https://doi.org/10.1177/0271678X15615132

    Article  CAS  Google Scholar 

  2. An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O et al (2018) Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimer’s Dement 14:318–329. https://doi.org/10.1016/J.JALZ.2017.09.011

    Article  Google Scholar 

  3. Auestad N, Korsak RA, Morrow JW, Edmond J (1991) Fatty acid oxidation and ketogenesis by astrocytes in primary culture. J Neurochem 56:1376–1386. https://doi.org/10.1111/j.1471-4159.1991.tb11435.x

    Article  CAS  PubMed  Google Scholar 

  4. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S (2011) Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 68:51–57. https://doi.org/10.1001/archneurol.2010.225

    Article  PubMed  Google Scholar 

  5. BONNEFONT J (2004) Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 25:495–520. https://doi.org/10.1016/j.mam.2004.06.004

    Article  CAS  PubMed  Google Scholar 

  6. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259. https://doi.org/10.1007/BF00308809

    Article  CAS  Google Scholar 

  7. Brandt J, Buchholz A, Henry-Barron B, Vizthum D, Avramopoulos D, Cervenka MC (2019) Preliminary report on the feasibility and efficacy of the modified atkins diet for treatment of mild cognitive impairment and early Alzheimer’s disease. J Alzheimer’s Dis 68:969–981. https://doi.org/10.3233/JAD-180995

    Article  CAS  Google Scholar 

  8. Buckley RF, Mormino EC, Rabin JS, Hohman TJ, Landau S, Hanseeuw BJ et al (2019) Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol 76:542. https://doi.org/10.1001/jamaneurol.2018.4693

    Article  PubMed  PubMed Central  Google Scholar 

  9. Casanova R, Varma S, Simpson B, Kim M, An Y, Saldana S et al (2016) Blood metabolite markers of preclinical Alzheimer’s disease in two longitudinally followed cohorts of older individuals. Alzheimer’s Dement 12:815–822. https://doi.org/10.1016/j.jalz.2015.12.008

    Article  Google Scholar 

  10. Castellano C-A, Nugent S, Paquet N, Tremblay S, Bocti C, Lacombe G et al (2014) Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer’s disease dementia. J Alzheimer’s Dis 43:1343–1353. https://doi.org/10.3233/JAD-141074

    Article  CAS  Google Scholar 

  11. Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G et al (2018) MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res 46:W486–W494. https://doi.org/10.1093/nar/gky310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chornenkyy Y, Wang W-X, Wei A, Nelson PT (2019) Alzheimer’s disease and type 2 diabetes mellitus are distinct diseases with potential overlapping metabolic dysfunction upstream of observed cognitive decline. Brain Pathol 29:3–17. https://doi.org/10.1111/bpa.12655

    Article  PubMed  Google Scholar 

  13. Croteau E, Castellano CA, Fortier M, Bocti C, Fulop T, Paquet N et al (2018) A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp Gerontol 107:18–26. https://doi.org/10.1016/j.exger.2017.07.004

    Article  CAS  PubMed  Google Scholar 

  14. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M et al (2016) Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Front Mol Neurosci 9:1–21. https://doi.org/10.3389/fnmol.2016.00053

    Article  CAS  Google Scholar 

  15. Demarest TG, McCarthy MM (2014) Sex differences in mitochondrial (dys)function: implications for neuroprotection. J Bioenerg Biomembr 47:173–188. https://doi.org/10.1007/s10863-014-9583-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Demarest TG, Schuh RA, Waite EL, Waddell J, McKenna MC, Fiskum G (2016) Sex dependent alterations in mitochondrial electron transport chain proteins following neonatal rat cerebral hypoxic-ischemia. J Bioenerg Biomembr 48:591–598. https://doi.org/10.1007/s10863-016-9678-4

    Article  CAS  PubMed  Google Scholar 

  17. Demarest TG, Waite EL, Kristian T, Puche AC, Waddell J, McKenna MC et al (2016) Sex-dependent mitophagy and neuronal death following rat neonatal hypoxia–ischemia. Neuroscience 335:103–113. https://doi.org/10.1016/j.neuroscience.2016.08.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eitan E, Hutchison ER, Marosi K, Comotto J, Mustapic M, Nigam SM et al (2016) Extracellular vesicle-associated Aβ mediates trans-neuronal bioenergetic and Ca2+-handling deficits in Alzheimer’s disease models. Aging Mech Dis 2:16019. https://doi.org/10.1038/npjamd.2016.19

    Article  Google Scholar 

  19. Fecher C, Trovò L, Müller SA, Snaidero N, Wettmarshausen J, Heink S et al (2019) Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity. Nat Neurosci. https://doi.org/10.1038/s41593-019-0479-z

    Article  PubMed  Google Scholar 

  20. Ferreira P, Villanueva R, Cabon L, Susin S, Medina M (2013) The Oxido-reductase Activity of the Apoptosis Inducing Factor: A Promising Pharmacological Tool? Curr Pharm Des 19:2628–2636. https://doi.org/10.2174/1381612811319140012

    Article  CAS  PubMed  Google Scholar 

  21. Ferretti MT, Iulita MF, Cavedo E, Chiesa PA, Schumacher Dimech A, Santuccione Chadha A et al (2018) Sex differences in Alzheimer disease—the gateway to precision medicine. Nat Rev Neurol 14:457–469. https://doi.org/10.1038/s41582-018-0032-9

    Article  PubMed  Google Scholar 

  22. Ferrucci L (2008) The baltimore longitudinal study of aging (BLSA): a 50-year-long journey and plans for the future. J Gerontol A Biol Sci Med Sci 63:1416–1419. https://doi.org/10.1093/gerona/63.12.1416

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fiehn O, Wohlgemuth G, Scholz M, Kind T, Lee DY, Lu Y et al (2008) Quality control for plant metabolomics: reporting MSI-compliant studies. Plant J 53:691–704. https://doi.org/10.1111/j.1365-313X.2007.03387.x

    Article  CAS  PubMed  Google Scholar 

  24. Fishman E (2017) Risk of developing dementia at older ages in the United States. Demography 54:1897–1919. https://doi.org/10.1007/s13524-017-0598-7

    Article  PubMed  PubMed Central  Google Scholar 

  25. Fransen M, Lismont C, Walton P (2017) The peroxisome-mitochondria connection: How and why? Int J Mol Sci 18:1126. https://doi.org/10.3390/ijms18061126

    Article  CAS  PubMed Central  Google Scholar 

  26. Gamaldo A, Moghekar A, Kilada S, Resnick SM, Zonderman AB, O’Brien R (2006) Effect of a clinical stroke on the risk of dementia in a prospective cohort. Neurology 67:1363–1369. https://doi.org/10.1212/01.wnl.0000240285.89067.3f

    Article  CAS  PubMed  Google Scholar 

  27. Gerondaes P, Alberti KGMM, Agius L (1988) Interactions of inhibitors of carnitine palmitoyltransferase I and fibrates in cultured hepatocytes. Biochem J 253:169–173. https://doi.org/10.1042/bj2530169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Grant P, Ahlemeyer B, Karnati S, Berg T, Stelzig I, Nenicu A et al (2013) The biogenesis protein PEX14 is an optimal marker for the identification and localization of peroxisomes in different cell types, tissues, and species in morphological studies. Histochem Cell Biol 140:423–442. https://doi.org/10.1007/s00418-013-1133-6

    Article  CAS  PubMed  Google Scholar 

  29. Guzmán M, Blázquez C (2001) Is there an astrocyte–neuron ketone body shuttle? Trends Endocrinol Metab 12:169–173. https://doi.org/10.1016/S1043-2760(00)00370-2

    Article  PubMed  Google Scholar 

  30. Hirayama A, Nakashima E, Sugimoto M, Akiyama SI, Sato W, Maruyama S et al (2012) Metabolic profiling reveals new serum biomarkers for differentiating diabetic nephropathy. Anal Bioanal Chem 404:3101–3109. https://doi.org/10.1007/s00216-012-6412-x

    Article  CAS  PubMed  Google Scholar 

  31. Horecker BL (2002) The pentose phosphate pathway. J Biol Chem 277:47965–47971. https://doi.org/10.1074/jbc.X200007200

    Article  CAS  PubMed  Google Scholar 

  32. Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E et al (2018) NAD + supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci 115:E1876–E1885. https://doi.org/10.1073/pnas.1718819115

    Article  CAS  PubMed  Google Scholar 

  33. Hu Y, Xu Q, Li K, Zhu H, Qi R, Zhang Z et al (2013) Gender differences of brain glucose metabolic networks revealed by FDG-PET: evidence from a large cohort of 400 young adults. PLoS ONE 8:e83821. https://doi.org/10.1371/journal.pone.0083821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hua X, Hibar DP, Lee S, Toga AW, Jack CR, Weiner MW et al (2010) Sex and age differences in atrophic rates: an ADNI study with n = 1368 MRI scans. Neurobiol Aging 31:1463–1480. https://doi.org/10.1016/j.neurobiolaging.2010.04.033

    Article  PubMed  PubMed Central  Google Scholar 

  35. Jadiya P, Kolmetzky DW, Tomar D, Di Meco A, Lombardi AA, Lambert JP et al (2019) Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease. Nat Commun 10:3885. https://doi.org/10.1038/s41467-019-11813-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kalaria RN, Harik SI (1989) Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease. J Neurochem 53:1083–1088. https://doi.org/10.1111/j.1471-4159.1989.tb07399.x

    Article  CAS  PubMed  Google Scholar 

  37. Karlstaedt A, Zhang X, Vitrac H, Harmancey R, Vasquez H, Wang JH et al (2016) Oncometabolite d-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart. Proc Natl Acad Sci 113:10436–10441. https://doi.org/10.1073/pnas.1601650113

    Article  CAS  PubMed  Google Scholar 

  38. Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman A (2000) Age-specific incidence rates of Alzheimer’s disease: the baltimore longitudinal study of aging. Neurology 54:2072–2077. https://doi.org/10.1212/wnl.54.11.2072

    Article  CAS  PubMed  Google Scholar 

  39. Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang L-J et al (1992) Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 59:776–779. https://doi.org/10.1111/j.1471-4159.1992.tb09439.x

    Article  CAS  PubMed  Google Scholar 

  40. Kristian T (2010) Isolation of mitochondria from the CNS. Curr Protoc Neurosci 52:1–12. https://doi.org/10.1002/0471142301.ns0722s52

    Article  Google Scholar 

  41. Lamont LS (2005) Gender differences in amino acid use during endurance exercise. Nutr Rev 63:419–422. https://doi.org/10.1301/nr.2005.dec.419-422

    Article  PubMed  Google Scholar 

  42. Liesinger AM, Graff-Radford NR, Duara R, Carter RE, Hanna Al-Shaikh FS, Koga S et al (2018) Sex and age interact to determine clinicopathologic differences in Alzheimer’s disease. Acta Neuropathol 136:873–885. https://doi.org/10.1007/s00401-018-1908-x

    Article  PubMed  PubMed Central  Google Scholar 

  43. Liu X, Kim CS, Kurbanov FT, Honzatko RB, Fromm HJ (1999) Dual mechanisms for glucose 6-phosphate inhibition of human brain hexokinase. J Biol Chem 274:31155–31159. https://doi.org/10.1074/jbc.274.44.31155

    Article  CAS  PubMed  Google Scholar 

  44. Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570:332–337. https://doi.org/10.1038/s41586-019-1195-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y et al (2010) Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology 75:764–770. https://doi.org/10.1212/WNL.0b013e3181eee25f

    Article  CAS  PubMed  Google Scholar 

  46. Maurer I, Zierz S, Möller HJ (1998) Carnitine acyltransferases are not changed in Alzheimer disease. Alzheimer Dis Assoc Disord 12:71–76. https://doi.org/10.1097/00002093-199806000-00003

    Article  CAS  PubMed  Google Scholar 

  47. McDade E, Bateman RJ (2017) Stop Alzheimer’s before it starts. Nature 547:153–155. https://doi.org/10.1038/547153a

    Article  CAS  PubMed  Google Scholar 

  48. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of alzheimer’s disease: report of the NINCDS-ADRDA work group⋆ under the auspices of department of health and human services task force on alzheimer’s disease. Neurology 34:939–944. https://doi.org/10.1212/wnl.34.7.939

    Article  CAS  PubMed  Google Scholar 

  49. Mielke MM, Ferretti MT, Iulita MF, Hayden K, Khachaturian AS (2018) Sex and gender in Alzheimer’s disease—Does it matter? Alzheimer’s Dement 14:1101–1103. https://doi.org/10.1016/j.jalz.2018.08.003

    Article  Google Scholar 

  50. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486. https://doi.org/10.1212/wnl.41.4.479

    Article  CAS  PubMed  Google Scholar 

  51. Monteiro-Cardoso VF, Oliveira MM, Melo T, Domingues MRM, Moreira PI, Ferreiro E et al (2014) Cardiolipin profile changes are associated to the early synaptic mitochondrial dysfunction in Alzheimer’s disease. J Alzheimer’s Dis 43:1375–1392. https://doi.org/10.3233/JAD-141002

    Article  CAS  Google Scholar 

  52. Moreira PI, Zhu X, Wang X, Lee H, Nunomura A, Petersen RB et al (2010) Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta Mol Basis Dis 1802:212–220. https://doi.org/10.1016/J.BBADIS.2009.10.007

    Article  CAS  Google Scholar 

  53. Morris JK, Honea RA, Vidoni ED, Swerdlow RH, Burns JM (2014) Is Alzheimer’s disease a systemic disease? Biochim Biophys Acta Mol Basis Dis 1842:1340–1349. https://doi.org/10.1016/j.bbadis.2014.04.012

    Article  CAS  Google Scholar 

  54. Mosconi L, Berti V, Quinn C, McHugh P, Petrongolo G, Varsavsky I et al (2017) Sex differences in Alzheimer risk. Neurology 89:1382–1390. https://doi.org/10.1212/WNL.0000000000004425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. O’Brien RJ, Resnick SM, Zonderman AB, Ferrucci L, Crain BJ, Pletnikova O et al (2009) Neuropathologic studies of the baltimore longitudinal study of aging (BLSA). J Alzheimer’s Dis 18:665–675. https://doi.org/10.3233/JAD-2009-1179

    Article  Google Scholar 

  56. Ota M, Matsuo J, Ishida I, Takano H, Yokoi Y, Hori H et al (2019) Effects of a medium-chain triglyceride-based ketogenic formula on cognitive function in patients with mild-to-moderate Alzheimer’s disease. Neurosci Lett 690:232–236. https://doi.org/10.1016/j.neulet.2018.10.048

    Article  CAS  PubMed  Google Scholar 

  57. Pandolfi PP, Sonati F, Rivi R, Mason P, Grosveld F, Luzzatto L (1995) Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase (G6PD): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress. EMBO J 14:5209–5215. https://doi.org/10.1002/j.1460-2075.1995.tb00205.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pichot P (1986) DSM-III: the 3d edition of the diagnostic and statistical manual of mental disorders from the American Psychiatric association. Rev Neurol (Paris) 142:489–99

  59. Prasad R, Çağlayan M, Dai D-P, Nadalutti CA, Zhao M-L, Gassman NR et al (2017) DNA polymerase β: a missing link of the base excision repair machinery in mammalian mitochondria. DNA Repair (Amst) 60:77–88. https://doi.org/10.1016/j.dnarep.2017.10.011

    Article  CAS  Google Scholar 

  60. Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD et al (2009) PGC-1α expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 66:352–361. https://doi.org/10.1001/archneurol.2008.588

    Article  PubMed  PubMed Central  Google Scholar 

  61. Petersen RC, Jack CR Jr, Xu Y-C, Waring SC, O’Brien PC, Smith GE et al (2012) Memory and MRI-based hippocampal volumes in aging and AD. Neurology 54:581–587. https://doi.org/10.1212/wnl.54.3.575

    Article  Google Scholar 

  62. Rex Sheu K-F, Kim Y-T, Blass JP, Weksler ME (1985) An immunochemical study of the pyruvate dehydrogenase deficit in Alzheimer’s disease brain. Ann Neurol 17:444–449. https://doi.org/10.1002/ana.410170505

    Article  Google Scholar 

  63. Rogers GW, Brand MD, Petrosyan S, Ashok D, Elorza AA, Ferrick DA et al (2011) High throughput microplate respiratory measurements using minimal quantities of isolated mitochondria. PLoS ONE. https://doi.org/10.1371/journal.pone.0021746

    Article  PubMed  PubMed Central  Google Scholar 

  64. Rolfes RJ (2006) Regulation of purine nucleotide biosynthesis: in yeast and beyond. Biochem Soc Trans 34:786–790. https://doi.org/10.1042/BST0340786

    Article  CAS  PubMed  Google Scholar 

  65. Seab JP, Jagust WJ, Wong STS, Roos MS, Reed BR, Budinger TF (1988) Quantitative NMR measurements of hippocampal atrophy in Alzheimer’s disease. Magn Reson Med 8:200–208. https://doi.org/10.1002/mrm.1910080210

    Article  CAS  PubMed  Google Scholar 

  66. Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P (1994) Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann Neurol 35:546–551. https://doi.org/10.1002/ana.410350507

    Article  CAS  PubMed  Google Scholar 

  67. Small GW, Kuhl DE, Riege WH, Fujikawa DG, Ashford JW, Metter EJ et al (1989) Cerebral glucose metabolic patterns in Alzheimer’s disease. Arch Gen Psychiatry 46:527. https://doi.org/10.1001/archpsyc.1989.01810060047008

    Article  CAS  PubMed  Google Scholar 

  68. Snowden SG, Ebshiana AA, Hye A, An Y, Pletnikova O, O’Brien R et al (2017) Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: a nontargeted metabolomic study. PLoS Med 14:e1002266. https://doi.org/10.1371/journal.pmed.1002266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sorbi S, Bird ED, Blass JP (1983) Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 13:72–78. https://doi.org/10.1002/ana.410130116

    Article  CAS  PubMed  Google Scholar 

  70. Sun A, Nguyen XV, Bing G (2002) Comparative analysis of an improved thioflavin-S stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections. J Histochem Cytochem 50:463–472. https://doi.org/10.1177/002215540205000403

    Article  CAS  PubMed  Google Scholar 

  71. Choi SW, Gerencser AA, Ng R, Flynn JM, Melov S, Danielson SR et al (2012) No consistent bioenergetic defects in presynaptic nerve terminals isolated from mouse models of Alzheimer’s disease. J Neurosci 32:16775–16784. https://doi.org/10.1016/j.freeradbiomed.2008.10.025.The

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Swerdlow RH, Burns JM, Khan SM (2010) The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimer’s Dis 20:S265–S279. https://doi.org/10.3233/JAD-2010-100339

    Article  CAS  Google Scholar 

  73. Sykora P, Kanno S, Akbari M, Kulikowicz T, Baptiste BA, Leandro GS et al (2017) DNA polymerase beta participates in mitochondrial DNA repair. Mol Cell Biol. https://doi.org/10.1128/MCB.00237-17

    Article  PubMed  PubMed Central  Google Scholar 

  74. Sykora P, Misiak M, Wang Y, Ghosh S, Leandro GS, Liu D et al (2015) DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res 43:943–959. https://doi.org/10.1093/nar/gku1356

    Article  CAS  PubMed  Google Scholar 

  75. Tarnopolsky MA (2000) Gender differences in substrate metabolism during endurance exercise. Can J Appl Physiol 25:312–327. https://doi.org/10.1139/h00-024

    Article  CAS  PubMed  Google Scholar 

  76. Taylor MK, Swerdlow RH, Sullivan DK (2019) Dietary neuroketotherapeutics for Alzheimer’s disease: an evidence update and the potential role for diet quality. Nutrients 11:1910. https://doi.org/10.3390/nu11081910

    Article  CAS  PubMed Central  Google Scholar 

  77. Tiwari M (2017) Glucose 6 phosphatase dehydrogenase (G6PD) and neurodegenerative disorders: mapping diagnostic and therapeutic opportunities. Genes Dis 4:196–203. https://doi.org/10.1016/j.gendis.2017.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Uchoa MF, Moser VA, Pike CJ (2016) Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors. Front Neuroendocrinol 43:60–82. https://doi.org/10.1016/j.yfrne.2016.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ulusu NN (2015) Glucose-6-phosphate dehydrogenase deficiency and Alzheimer’s disease: Partners in crime? The hypothesis. Med Hypotheses 85:219–223. https://doi.org/10.1016/j.mehy.2015.05.006

    Article  CAS  PubMed  Google Scholar 

  80. Varma VR, Oommen AM, Varma S, Casanova R, An Y, Andrews RM et al (2018) Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: a targeted metabolomics study. PLoS Med. https://doi.org/10.1371/journal.pmed.1002482

    Article  PubMed  PubMed Central  Google Scholar 

  81. Viña J, Lloret A (2010) Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-β peptide. J Alzheimer’s Dis 20:527–533. https://doi.org/10.3233/JAD-2010-100501

    Article  CAS  Google Scholar 

  82. Violante S, Achetib N, van Roermund CWT, Hagen J, Dodatko T, Vaz FM et al (2019) Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4. FASEB J 33:4355–4364. https://doi.org/10.1096/fj.201801498r

    Article  CAS  PubMed  Google Scholar 

  83. Wei X, Yang H, Liu Y, Yang Y, Wang P, Kim S-H et al (2011) Oncometabolite 2-hydroxygulatatrate is a competitive inhibitor of a-KG dependent dioxygenase. Cancer Cell 19:17–30. https://doi.org/10.1016/j.ccr.2010.12.014.Xu

    Article  CAS  Google Scholar 

  84. Weissman L, Jo DG, Sørensen MM, de Souza-Pinto NC, Markesbery WR, Mattson MP et al (2007) Defective DNA base excision repair in brain from individuals with Alzheimer’s disease and amnestic mild cognitive impairment. Nucleic Acids Res 35:5545–5555. https://doi.org/10.1093/nar/gkm605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Widdowson EM (1976) The response of the sexes to nutritional stress. Proc Nutr Soc 35:175. https://doi.org/10.2307/465275

    Article  CAS  PubMed  Google Scholar 

  86. Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K, Wheeler ML et al (2016) Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell 166:624–636. https://doi.org/10.1016/j.cell.2016.05.076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Xia J, Psychogios N, Young N, Wishart DS (2009) MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Res 37:652–660. https://doi.org/10.1093/nar/gkp356

    Article  CAS  Google Scholar 

  88. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad USA 106:14670–14675. https://doi.org/10.1073/pnas.0903563106

    Article  Google Scholar 

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institutes on Aging, National Institutes of Health. The authors are grateful to the Baltimore Longitudinal Study of Aging study participants and staff for their dedication to these studies. We would like to thank Kelly Palagia (West coast metabolomics center, UC Davis) for performing the GC-TOF plasma metabolomics and Drs. Jong-Hyuk Lee and Anthony Moore for their critical review of the manuscript.

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Authors and Affiliations

  1. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Tyler G. Demarest, Darlene Estrada, Mansi Babbar, Sambuddha Basu, Deborah L. Croteau & Vilhelm A. Bohr

  2. Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Tyler G. Demarest & Mark P. Mattson

  3. Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    Vijay R. Varma, Uma V. Mahajan & Madhav Thambisetty

  4. Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA

    Ruin Moaddel

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Demarest, T.G., Varma, V.R., Estrada, D. et al. Biological sex and DNA repair deficiency drive Alzheimer’s disease via systemic metabolic remodeling and brain mitochondrial dysfunction. Acta Neuropathol 140, 25–47 (2020). https://doi.org/10.1007/s00401-020-02152-8

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  • DOI: https://doi.org/10.1007/s00401-020-02152-8

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