{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:53:02Z","timestamp":1791431582321,"version":"4.3.3"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"NIH","award":["R01 AG054523"],"award-info":[{"award-number":["R01 AG054523"]}]},{"name":"NIH","award":["R01 AG061805"],"award-info":[{"award-number":["R01 AG061805"]}]},{"name":"NIH","award":["P30 AG068635"],"award-info":[{"award-number":["P30 AG068635"]}]},{"name":"NIH","award":["P30 AG 072947"],"award-info":[{"award-number":["P30 AG 072947"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["GeroScience"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Systemic mitochondrial dysfunction is apparent in the pathophysiology of Alzheimer\u2019s disease (AD). However, the factors driving bioenergetic decline remain unclear. This study utilized serum samples from older adults with normal cognition, mild cognitive impairment, and dementia to identify circulating molecules that can drive mitochondrial dysfunction in the context of AD. We used mass spectrometry to measure the abundance of lipid metabolites and applied tiered selection criteria to identify candidate \u201cmito-inhibitory\u201d molecules. These criteria were based on correlations with (1) in vitro bioenergetic effects of whole serum samples on na\u00efve cells, (2) the bioenergetic capacity of blood cells from the serum donor, and (3) cognition, as measured by the modified mini-mental state exam. Mito-inhibitory lipid candidates were validated by examining their bioenergetic effects on neurons, myoblasts, and fibroblasts in vitro. Our results indicate that nervonic acid and 15-epi Prostaglandin A1 (15-epi-PGA1) are elevated in participants with dementia compared to those with normal cognition. Importantly, both metabolites inhibited mitochondrial function across multiple cell types in vitro. High resolution respirometric analyses reveal that inhibitory effects from lipid treatment occur via broad inhibition of the electron transfer system (ETS) with no change in overall mitochondrial content. This study provides insights into the mechanisms underlying systemic bioenergetic decline associated with AD dementia. The identification of circulating factors that drive mitochondrial bioenergetic decline may inform the development of mitochondrial therapeutics for AD.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>In this study, we describe the identification and validation of mito-inhibitory bioactive lipid metabolites through a combination of serum lipidomics, statistical analyses, and mitochondrial respirometry.<\/jats:p>","DOI":"10.1007\/s11357-025-01776-6","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T23:27:24Z","timestamp":1752190044000},"page":"2327-2343","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Nervonic acid and 15-epi-PGA1 mediate systemic mitochondrial dysfunction in AD dementia"],"prefix":"10.1007","volume":"48","author":[{"given":"Stephanie Robyn","family":"Heimler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Allison","family":"Amick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn","family":"Bergstrom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Molin\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gargi","family":"Mahapatra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Craft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5786-4622","authenticated-orcid":false,"given":"Anthony J. A.","family":"Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"issue":"6","key":"1776_CR1","doi-asserted-by":"publisher","first-page":"2179","DOI":"10.1046\/j.1471-4159.1994.63062179.x","volume":"63","author":"EM Mutisya","year":"1994","unstructured":"Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer\u2019s disease. J Neurochem. 1994;63(6):2179\u201384.","journal-title":"J Neurochem"},{"issue":"49","key":"1776_CR2","doi-asserted-by":"publisher","first-page":"19318","DOI":"10.1073\/pnas.0804871105","volume":"105","author":"X Wang","year":"2008","unstructured":"Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, et al. Amyloid-\u03b2 overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission\/fusion proteins. Proc Natl Acad Sci. 2008Dec 9;105(49):19318\u201323.","journal-title":"Proc Natl Acad Sci"},{"issue":"1","key":"1776_CR3","doi-asserted-by":"publisher","first-page":"14038","DOI":"10.1038\/s41598-017-14420-x","volume":"7","author":"KC Sonntag","year":"2017","unstructured":"Sonntag KC, Ryu WI, Amirault KM, Healy RA, Siegel AJ, McPhie DL, et al. Late-onset Alzheimer\u2019s disease is associated with inherent changes in bioenergetics profiles. Sci Rep. 2017Oct 25;7(1):14038.","journal-title":"Sci Rep"},{"issue":"4","key":"1776_CR4","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.3233\/JAD-160841","volume":"55","author":"L Szablewski","year":"2017","unstructured":"Szablewski L. Glucose transporters in brain: in health and in Alzheimer\u2019s disease. J Alzheimers Dis. 2017Jan 1;55(4):1307\u201320.","journal-title":"J Alzheimers Dis"},{"key":"1776_CR5","doi-asserted-by":"crossref","unstructured":"Mart\u00edn-Maestro P, Gargini R, A Sproul A, Garc\u00eda E, Ant\u00f3n LC, Noggle S, et al. Mitophagy failure in fibroblasts and iPSC-derived neurons of Alzheimer\u2019s disease-associated presenilin 1 mutation. Front Mol Neurosci. 2017;10:291.","DOI":"10.3389\/fnmol.2017.00291"},{"issue":"1","key":"1776_CR6","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1007\/s12035-012-8300-y","volume":"46","author":"K Leuner","year":"2012","unstructured":"Leuner K, Schulz K, Sch\u00fctt T, Pantel J, Prvulovic D, Rhein V, et al. Peripheral mitochondrial dysfunction in Alzheimer\u2019s disease: focus on lymphocytes. Mol Neurobiol. 2012Aug;46(1):194\u2013204.","journal-title":"Mol Neurobiol"},{"issue":"6","key":"1776_CR7","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1007\/s11064-018-2657-x","volume":"44","author":"FA Prestia","year":"2019","unstructured":"Prestia FA, Galeano P, Martino Adami PV, Do Carmo S, Casta\u00f1o EM, Cuello AC, et al. Platelets bioenergetics screening reflects the impact of brain A\u03b2 plaque accumulation in a rat model of Alzheimer. Neurochem Res. 2019Jun;44(6):1375\u201386.","journal-title":"Neurochem Res"},{"key":"1776_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/5923938","volume":"2016","author":"A Delbarba","year":"2016","unstructured":"Delbarba A, Abate G, Prandelli C, Marziano M, Buizza L, Arce Varas N, et al. Mitochondrial alterations in peripheral mononuclear blood cells from Alzheimer\u2019s disease and mild cognitive impairment patients. Oxid Med Cell Longev. 2016;2016:1\u201311.","journal-title":"Oxid Med Cell Longev"},{"issue":"3","key":"1776_CR9","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1093\/gerona\/glaa299","volume":"76","author":"JL Gonzalez-Armenta","year":"2021","unstructured":"Gonzalez-Armenta JL, Li N, Lee RL, Lu B, Molina AJA. Heterochronic parabiosis: old blood induces changes in mitochondrial structure and function of young mice. J Gerontol A Biol Sci Med Sci. 2021Feb 25;76(3):434\u20139.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"1776_CR10","doi-asserted-by":"crossref","unstructured":"Mahapatra G, Gao Z, Bateman JR 3rd, Lockhart SN, Bergstrom J, DeWitt AR, Piloso JE, Kramer PA, Gonzalez-Armenta JL, Amick KA, Casanova R, Craft S, Molina AJA. Blood-based bioenergetic profiling reveals differences in mitochondrial function associated with cognitive performance and Alzheimer's disease. Alzheimers Dement. 2023.","DOI":"10.1002\/alz.12731"},{"key":"1776_CR11","doi-asserted-by":"crossref","unstructured":"Keenan A, Walker RC, Hoogeveen AR, Folsom CM, Ballantyne DS, Knopman B, Windham G, et al. Midlife systemic inflammatory markers are associated with late-life brain volume. Neurology. 2017;89(22):2262.","DOI":"10.1212\/WNL.0000000000004688"},{"issue":"1","key":"1776_CR12","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s13195-015-0117-2","volume":"7","author":"C Cunningham","year":"2015","unstructured":"Cunningham C, Hennessy E. Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research. Alzheimers Res Ther. 2015Dec;7(1):33.","journal-title":"Alzheimers Res Ther"},{"issue":"2","key":"1776_CR13","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.plipres.2007.12.002","volume":"47","author":"K Nagao","year":"2008","unstructured":"Nagao K, Yanagita T. Bioactive lipids in metabolic syndrome. Prog Lipid Res. 2008Mar;47(2):127\u201346.","journal-title":"Prog Lipid Res"},{"key":"1776_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/946813","volume":"2012","author":"IVDA Lima","year":"2012","unstructured":"Lima IVDA, Bastos LFS, Limbor\u00e7o-Filho M, Fiebich BL, De Oliveira ACP. Role of prostaglandins in neuroinflammatory and neurodegenerative diseases. Mediators Inflamm. 2012;2012:1\u201313.","journal-title":"Mediators Inflamm"},{"issue":"10","key":"1776_CR15","doi-asserted-by":"publisher","first-page":"2774","DOI":"10.1172\/JCI25420","volume":"115","author":"WJ Lukiw","year":"2005","unstructured":"Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest. 2005Oct;115(10):2774\u201383.","journal-title":"J Clin Invest"},{"issue":"1","key":"1776_CR16","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/s41398-021-01362-2","volume":"11","author":"Y Liu","year":"2021","unstructured":"Liu Y, Thalamuthu A, Mather KA, Crawford J, Ulanova M, Wong MWK, et al. Plasma lipidome is dysregulated in Alzheimer\u2019s disease and is associated with disease risk genes. Transl Psychiatry. 2021Jun 7;11(1):344.","journal-title":"Transl Psychiatry"},{"key":"1776_CR17","doi-asserted-by":"crossref","unstructured":"Barupal DK, Baillie R, Fan S, Saykin AJ, Meikle PJ, Arnold M, et al. Sets of coregulated serum lipids are associated with Alzheimer\u2019s disease pathophysiology. Zetterberg H, editor. Alzheimers Dement Diagn Assess Dis Monit. 2019;11(1):619\u201327.","DOI":"10.1016\/j.dadm.2019.07.002"},{"key":"1776_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.954090","volume":"14","author":"KA Amick","year":"2022","unstructured":"Amick KA, Mahapatra G, Gao Z, Dewitt A, Craft S, Jain M, et al. Plasma glycocholic acid and linoleic acid identified as potential mediators of mitochondrial bioenergetics in Alzheimer\u2019s dementia. Front Aging Neurosci. 2022;14: 954090.","journal-title":"Front Aging Neurosci"},{"issue":"5","key":"1776_CR19","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1111\/ene.15246","volume":"29","author":"T Terada","year":"2022","unstructured":"Terada T, Therriault J, Kang MS, Savard M, Pascoal TA, Lussier F, et al. Mitochondrial complex I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer\u2019s disease. Eur J Neurol. 2022May;29(5):1324\u201334.","journal-title":"Eur J Neurol"},{"issue":"1","key":"1776_CR20","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3233\/JAD-180337","volume":"66","author":"TL Emmerzaal","year":"2018","unstructured":"Emmerzaal TL, Rodenburg RJ, Tanila H, Verweij V, Kiliaan AJ, Kozicz T. Age-dependent decrease of mitochondrial complex II activity in a familial mouse model for Alzheimer\u2019s disease. J Alzheimers Dis. 2018Oct 16;66(1):75\u201382.","journal-title":"J Alzheimers Dis"},{"issue":"5","key":"1776_CR21","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1007\/s11357-021-00426-x","volume":"43","author":"GS Shadel","year":"2021","unstructured":"Shadel GS, Adams PD, Berggren WT, Diedrich JK, Diffenderfer KE, Gage FH, et al. The San Diego Nathan Shock Center: tackling the heterogeneity of aging. GeroScience. 2021Oct;43(5):2139\u201348.","journal-title":"GeroScience"},{"issue":"2","key":"1776_CR22","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/0090-6980(74)90128-2","volume":"7","author":"P Pletka","year":"1974","unstructured":"Pletka P, Hickler RB. Blood prostaglandin A (PGA) levels in normal human subjects. Prostaglandins. 1974Jul;7(2):107\u201315.","journal-title":"Prostaglandins"},{"issue":"1","key":"1776_CR23","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1515\/biol-2019-0026","volume":"14","author":"M Szczuko","year":"2019","unstructured":"Szczuko M, Drozd A, Maciejewska D, Zapa\u0142owska-Chwy\u0107 M, Stachowska E. Decrease in the level of nervonic acid and increased gamma linolenic acid in the plasma of women with polycystic ovary syndrome after a three-month low-glycaemic index and caloric reduction diet. Open Life Sci. 2019Jul 10;14(1):224\u201336.","journal-title":"Open Life Sci"},{"issue":"3","key":"1776_CR24","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/ijnp\/pyx089","volume":"21","author":"Y Kageyama","year":"2018","unstructured":"Kageyama Y, Kasahara T, Nakamura T, Hattori K, Deguchi Y, Tani M, et al. Plasma nervonic acid is a potential biomarker for major depressive disorder: a pilot study. Int J Neuropsychopharmacol. 2018Mar 1;21(3):207\u201315.","journal-title":"Int J Neuropsychopharmacol"},{"issue":"2","key":"1776_CR25","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/0090-6980(79)90046-7","volume":"17","author":"PL Taylor","year":"1979","unstructured":"Taylor PL. The 8-isoprostaglandins: evidence for eight compounds in human semen. Prostaglandins. 1979Feb;17(2):259\u201367.","journal-title":"Prostaglandins"},{"issue":"5","key":"1776_CR26","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/j.neurobiolaging.2003.12.023","volume":"25","author":"J Raber","year":"2004","unstructured":"Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging. 2004May 1;25(5):641\u201350.","journal-title":"Neurobiol Aging"},{"issue":"3","key":"1776_CR27","first-page":"193","volume":"1","author":"C Lovati","year":"2010","unstructured":"Lovati C, Galimberti D, Albani D, Bertora P, Venturelli E, Cislaghi G, et al. APOE \u03b52 and \u03b54 influence the susceptibility for Alzheimer\u2019s disease but not other dementias. Int J Mol Epidemiol Genet. 2010Apr 5;1(3):193\u2013200.","journal-title":"Int J Mol Epidemiol Genet"},{"issue":"1","key":"1776_CR28","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/1471-2202-15-24","volume":"15","author":"RA Schuh","year":"2014","unstructured":"Schuh RA, Jackson KC, Schlappal AE, Spangenburg EE, Ward CW, Park JH, et al. Mitochondrial oxygen consumption deficits in skeletal muscle isolated from an Alzheimer\u2019s disease-relevant murine model. BMC Neurosci. 2014Dec;15(1):24.","journal-title":"BMC Neurosci"},{"key":"1776_CR29","doi-asserted-by":"crossref","unstructured":"Morris JK, McCoin CS, Fuller KN, John CS, Wilkins HM, Green ZD, et al. Mild cognitive impairment and donepezil impact mitochondrial respiratory capacity in skeletal muscle. Function. 2021;2(6):zqab045.","DOI":"10.1093\/function\/zqab045"},{"issue":"40","key":"1776_CR30","doi-asserted-by":"publisher","first-page":"12772","DOI":"10.1021\/acs.jafc.2c05770","volume":"70","author":"F Liu","year":"2022","unstructured":"Liu F, Wu R, Ma X, Su E. The advancements and prospects of nervonic acid production. J Agric Food Chem. 2022Oct 12;70(40):12772\u201383.","journal-title":"J Agric Food Chem"},{"key":"1776_CR31","doi-asserted-by":"crossref","unstructured":"Astarita G, Jung KM, Vasilevko V, DiPatrizio NV, Martin SK, Cribbs DH, et al. Elevated stearoyl-CoA desaturase in brains of patients with Alzheimer\u2019s disease. Gaetani S, editor. PLoS ONE. 2011;6(10):e24777.","DOI":"10.1371\/journal.pone.0024777"},{"issue":"12","key":"1776_CR32","first-page":"1502","volume":"1862","author":"V Vozella","year":"2017","unstructured":"Vozella V, Basit A, Misto A, Piomelli D. Age-dependent changes in nervonic acid-containing sphingolipids in mouse hippocampus. Biochim Biophys Acta BBA - Mol Cell Biol Lipids. 2017Dec;1862(12):1502\u201311.","journal-title":"Biochim Biophys Acta BBA - Mol Cell Biol Lipids"},{"issue":"10","key":"1776_CR33","doi-asserted-by":"publisher","first-page":"5989","DOI":"10.1002\/fsn3.3533","volume":"11","author":"M Aihaiti","year":"2023","unstructured":"Aihaiti M, Shi H, Liu Y, Hou C, Song X, Li M, et al. Nervonic acid reduces the cognitive and neurological disturbances induced by combined doses of D-galactose\/AlCl in mice. Food Sci Nutr. 2023;11(10):5989\u201398.","journal-title":"Food Sci Nutr"},{"issue":"1","key":"1776_CR34","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1002\/jnr.10726","volume":"74","author":"AJ Hanson","year":"2003","unstructured":"Hanson AJ, Prasad JE, Nahreini P, Andreatta C, Kumar B, Yan XD, et al. Overexpression of amyloid precursor protein is associated with degeneration, decreased viability, and increased damage caused by neurotoxins (prostaglandins A1 and E2, hydrogen peroxide, and nitric oxide) in differentiated neuroblastoma cells. J Neurosci Res. 2003Oct 1;74(1):148\u201359.","journal-title":"J Neurosci Res"},{"issue":"1","key":"1776_CR35","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s40035-023-00366-w","volume":"12","author":"H Nango","year":"2023","unstructured":"Nango H, Tsuruta K, Miyagishi H, Aono Y, Saigusa T, Kosuge Y. Update on the pathological roles of prostaglandin E2 in neurodegeneration in amyotrophic lateral sclerosis. Transl Neurodegener. 2023Jun 19;12(1):32.","journal-title":"Transl Neurodegener"},{"issue":"4","key":"1776_CR36","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1046\/j.1471-4159.1995.64041645.x","volume":"64","author":"MB Mattammal","year":"2002","unstructured":"Mattammal MB, Strong R, Lakshmi VM, Chung HD, Stephenson AH. Prostaglandin H synthetase-mediated metabolism of dopamine: implication for Parkinson\u2019s disease. J Neurochem. 2002Nov 23;64(4):1645\u201354.","journal-title":"J Neurochem"},{"key":"1776_CR37","doi-asserted-by":"crossref","unstructured":"Zeng X, Fan X, Yu H, Cai S, Zhou L, Wu H, et al. Nervonic acid triggered ovarian inflammation by inducing mitochondrial oxidative stress to activate NLRP3\/ IL-1\u03b2 pathway. J Adv Res [Internet]. 2024 [cited 2025 Apr 18]. Available from: https:\/\/www.sciencedirect.com\/science\/article\/pii\/S2090123224003710","DOI":"10.1016\/j.jare.2024.08.028"},{"issue":"15","key":"1776_CR38","doi-asserted-by":"publisher","first-page":"12076","DOI":"10.1074\/jbc.M009630200","volume":"276","author":"M Kondo","year":"2001","unstructured":"Kondo M, Oya-Ito T, Kumagai T, Osawa T, Uchida K. Cyclopentenone prostaglandins as potential inducers of intracellular oxidative stress *. J Biol Chem. 2001Apr 13;276(15):12076\u201383.","journal-title":"J Biol Chem"},{"issue":"5","key":"1776_CR39","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/s10059-010-0157-1","volume":"30","author":"S Basu","year":"2010","unstructured":"Basu S. Bioactive eicosanoids: role of prostaglandin F2\u03b1 and F2-isoprostanes in inflammation and oxidative stress related pathology. Mol Cells. 2010Nov 1;30(5):383\u201391.","journal-title":"Mol Cells"},{"key":"1776_CR40","doi-asserted-by":"crossref","unstructured":"Plewes MR, Przygrodzka E, Monaco CF, Snider AP, Keane JA, Burns PD, et al. Prostaglandin F2\u03b1 regulates mitochondrial dynamics and mitophagy in the bovine corpus luteum. Life Sci Alliance [Internet]. 2023 [cited 2025 Apr 18]:6(7). Available from: https:\/\/www.life-science-alliance.org\/content\/6\/7\/e202301968","DOI":"10.26508\/lsa.202301968"},{"key":"1776_CR41","doi-asserted-by":"publisher","unstructured":"Figueiredo-Pereira ME, Rockwell P, Schmidt-Glenewinkel T, Serrano P. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration. Front Mol Neurosci [Internet]. 2015 [cited 2025 Apr 18];7. Available from: https:\/\/www.frontiersin.orghttps:\/\/www.frontiersin.org\/journals\/molecular-neuroscience\/articles\/https:\/\/doi.org\/10.3389\/fnmol.2014.00104\/full","DOI":"10.3389\/fnmol.2014.00104\/full"},{"key":"1776_CR42","doi-asserted-by":"crossref","unstructured":"Parker WD, BA JP, Filley CM, Kleinschmidt-DeMasters BK. Electron transport chain defects in Alzheimer\u2019s disease brain. Neurology. 1994 Jun;44(6):1090\u20131090.","DOI":"10.1212\/WNL.44.6.1090"},{"issue":"6","key":"1776_CR43","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.bbabio.2009.02.028","volume":"1787","author":"H Seelert","year":"2009","unstructured":"Seelert H, Dani DN, Dante S, Hau\u00df T, Krause F, Sch\u00e4fer E, et al. From protons to OXPHOS supercomplexes and Alzheimer\u2019s disease: structure\u2013dynamics\u2013function relationships of energy-transducing membranes. Biochim Biophys Acta BBA - Bioenerg. 2009Jun 1;1787(6):657\u201371.","journal-title":"Biochim Biophys Acta BBA - Bioenerg"},{"issue":"1","key":"1776_CR44","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/S0197-4580(03)00033-2","volume":"25","author":"SM Cardoso","year":"2004","unstructured":"Cardoso SM, Proen\u00e7a MT, Santos S, Santana I, Oliveira CR. Cytochrome c oxidase is decreased in Alzheimer\u2019s disease platelets. Neurobiol Aging. 2004Jan 1;25(1):105\u201310.","journal-title":"Neurobiol Aging"},{"issue":"4","key":"1776_CR45","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.mito.2013.03.008","volume":"13","author":"A Bobba","year":"2013","unstructured":"Bobba A, Amadoro G, Valenti D, Corsetti V, Lassandro R, Atlante A. Mitochondrial respiratory chain complexes I and IV are impaired by \u03b2-amyloid via direct interaction and through complex I-dependent ROS production, respectively. Mitochondrion. 2013Jul 1;13(4):298\u2013311.","journal-title":"Mitochondrion"},{"issue":"6","key":"1776_CR46","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1007\/s10571-009-9398-y","volume":"29","author":"V Rhein","year":"2009","unstructured":"Rhein V, Baysang G, Rao S, Meier F, Bonert A, M\u00fcller-Spahn F, et al. Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells. Cell Mol Neurobiol. 2009Sep 1;29(6):1063\u201371.","journal-title":"Cell Mol Neurobiol"},{"issue":"4","key":"1776_CR47","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.jalz.2009.02.006","volume":"5","author":"K Nichol","year":"2009","unstructured":"Nichol K, Deeny SP, Seif J, Camaclang K, Cotman CW. Exercise improves cognition and hippocampal plasticity in APOE \u03b54 mice. Alzheimers Dement. 2009Jul 1;5(4):287\u201394.","journal-title":"Alzheimers Dement"},{"key":"1776_CR48","doi-asserted-by":"crossref","unstructured":"Li L, Wang Z, Zuo Z. Chronic intermittent fasting improves cognitive functions and brain structures in mice. Xie Z, editor. PLoS ONE. 2013 Jun 3;8(6):e66069.","DOI":"10.1371\/journal.pone.0066069"},{"issue":"8","key":"1776_CR49","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1007\/s11306-022-01908-5","volume":"18","author":"JV de Seymour","year":"2022","unstructured":"de Seymour JV, Beck KL, Conlon CA, von Hurst PR, Mumme KD, Haskell-Ramsay CF, et al. Plasma nervonic acid levels were negatively associated with attention levels in community-living older adults in New Zealand. Metabolomics. 2022Jul 16;18(8):54.","journal-title":"Metabolomics"},{"issue":"10","key":"1776_CR50","doi-asserted-by":"publisher","first-page":"4436","DOI":"10.1002\/alz.13388","volume":"19","author":"Q Tian","year":"2023","unstructured":"Tian Q, Bilgel M, Walker KA, Moghekar AR, Fishbein KW, Spencer RG, et al. Skeletal muscle mitochondrial function predicts cognitive impairment and is associated with biomarkers of Alzheimer\u2019s disease and neurodegeneration. Alzheimers Dement. 2023;19(10):4436\u201345.","journal-title":"Alzheimers Dement"},{"key":"1776_CR51","unstructured":"F. Monteiro-Cardoso V, Castro M, Oliveira MM, I. Moreira P, Peixoto F, A. Videira R. Age-dependent biochemical dysfunction in skeletal muscle of triple- transgenic mouse model of Alzheimer\u2019s disease [Internet]. Bentham Science Publishers; 2015 [cited 2025 Apr 18]. Available from: https:\/\/www.ingentaconnect.com\/content\/ben\/car\/2015\/00000012\/00000002\/art00003"},{"issue":"2","key":"1776_CR52","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13552","volume":"21","author":"Q Tian","year":"2022","unstructured":"Tian Q, Mitchell BA, Zampino M, Fishbein KW, Spencer RG, Ferrucci L. Muscle mitochondrial energetics predicts mobility decline in well-functioning older adults: The baltimore longitudinal study of aging. Aging Cell. 2022Feb;21(2): e13552.","journal-title":"Aging Cell"},{"issue":"1","key":"1776_CR53","doi-asserted-by":"publisher","first-page":"4773","DOI":"10.1038\/s41467-021-24956-2","volume":"12","author":"L Grevendonk","year":"2021","unstructured":"Grevendonk L, Connell NJ, McCrum C, Fealy CE, Bilet L, Bruls YMH, et al. Impact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and physical function. Nat Commun. 2021Aug 6;12(1):4773.","journal-title":"Nat Commun"},{"issue":"6","key":"1776_CR54","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1001\/jamacardio.2023.0957","volume":"8","author":"L Scandalis","year":"2023","unstructured":"Scandalis L, Kitzman DW, Nicklas BJ, Lyles M, Brubaker P, Nelson MB, et al. Skeletal muscle mitochondrial respiration and exercise intolerance in patients with heart failure with preserved ejection fraction. JAMA Cardiol. 2023Jun 1;8(6):575\u201384.","journal-title":"JAMA Cardiol"},{"issue":"10","key":"1776_CR55","doi-asserted-by":"publisher","first-page":"4436","DOI":"10.1002\/alz.13388","volume":"19","author":"Q Tian","year":"2023","unstructured":"Tian Q, Bilgel M, Walker KA, Moghekar AR, Fishbein KW, Spencer RG, et al. Skeletal muscle mitochondrial function predicts cognitive impairment and is associated with biomarkers of Alzheimer\u2019s disease and neurodegeneration. Alzheimers Dement J Alzheimers Assoc. 2023Oct;19(10):4436\u201345.","journal-title":"Alzheimers Dement J Alzheimers Assoc"},{"issue":"10","key":"1776_CR56","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1007\/s11745-998-0297-4","volume":"33","author":"C Cook","year":"1998","unstructured":"Cook C, Barnett J, Coupland K, Sargent J. Effects of feeding Lunaria oil rich in nervonic and erucic acids on the fatty acid compositions of sphingomyelins from erythrocytes, liver, and brain of the quaking mouse mutant. Lipids. 1998Oct;33(10):993\u20131000.","journal-title":"Lipids"},{"issue":"9","key":"1776_CR57","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1007\/s11095-021-03098-6","volume":"38","author":"EM Rhea","year":"2021","unstructured":"Rhea EM, Banks WA. Interactions of lipids, lipoproteins, and apolipoproteins with the blood-brain barrier. Pharm Res. 2021Sep;38(9):1469\u201375.","journal-title":"Pharm Res"},{"issue":"2","key":"1776_CR58","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jfma.2015.08.004","volume":"115","author":"YF Shea","year":"2016","unstructured":"Shea YF, Chu LW, Chan AOK, Ha J, Li Y, Song YQ. A systematic review of familial Alzheimer\u2019s disease: differences in presentation of clinical features among three mutated genes and potential ethnic differences. J Formos Med Assoc. 2016Feb 1;115(2):67\u201375.","journal-title":"J Formos Med Assoc"},{"issue":"2","key":"1776_CR59","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s10048-005-0211-x","volume":"6","author":"U Finckh","year":"2005","unstructured":"Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, et al. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005May 1;6(2):85\u20139.","journal-title":"Neurogenetics"}],"container-title":["GeroScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01776-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11357-025-01776-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01776-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:05:05Z","timestamp":1773050705000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11357-025-01776-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,11]]},"references-count":59,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["1776"],"URL":"https:\/\/doi.org\/10.1007\/s11357-025-01776-6","relation":{},"ISSN":["2509-2723"],"issn-type":[{"value":"2509-2723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,11]]},"assertion":[{"value":"11 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All human subjects provided informed consent. This study utilized the Wake Forest School of Medicine\u2019s Alzheimer\u2019s Disease Clinical Core (ADCC) cohort (IRB00025540; Title: Alzheimer\u2019s Disease Clinical Core\/\u201cThe Healthy Brain Study\u201d; approval date: 1\u20138-2014\/6\u20135-2024).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"We consent to the publishing agreement.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}