{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:52:32Z","timestamp":1790196752156,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,1]]},"abstract":"ABSTRACT<\/jats:title>\n \n Alzheimer disease is a neurodegenerative pathology\u2010modifying mitochondrial metabolism with energy impairments where the effects of biological sex and DNA repair deficiencies are unclear. We investigated the therapeutic potential of dietary ketosis alone or with supplemental nicotinamide riboside (NR) on hippocampal intermediary metabolism and mitochondrial bioenergetics in older male and female wild\u2010type (Wt) and 3xTgAD\u2010DNA polymerase\u2010\u03b2\u2010deficient (3xTg\/POL\u03b2\n +\/\u2212<\/jats:sup>\n ) (AD) mice. DNA polymerase\u2010\u03b2 is a key enzyme in DNA base excision repair (BER) of oxidative damage that may also contribute to mitochondrial DNA repair. Metabolic alterations imparted by ketosis and\/or NR were assessed in 16 male and female groups, 4 Wt and 4 AD. At 73\u2009weeks of age, mice were divided into: (A) carbohydrate diet (Carb); (B) Carb diet with NR (Carb\u2010NR); (C) Ket diet (Ket); and (D) Ket diet with NR (Ket\u2010NR) groups and remained on their respective treatments for 12\u2009weeks. Mice were euthanized and hippocampi were rapidly removed and frozen. Glycolytic and TCA cycle intermediates were determined by quantitative GC\u2013MS and the ratios of the mitochondrial free [NAD\n ox<\/jats:sub>\n ]\/[NADH\n red<\/jats:sub>\n ] and coenzyme ubiquinone (CoQ\/CoQH\n 2<\/jats:sub>\n ) couples and the Gibbs free energy of the Complex I\u2013II system of the electron transport chain (ETC) () were calculated from selected metabolites. Mice in Groups C and D had elevated blood ketones (1\u20132\u2009mM). In most groupings, male mice had higher concentrations of TCA cycle intermediates than females. Moreover, higher concentrations of fumarate in Wt males were associated with elevations in the \u0394\n G<\/jats:italic>\n \u2032 of Complex I\u2013II compared to females. In Wt males, NR treatments were associated with elevated concentrations of \u03b1\u2010ketoglutarate and malate and linked to increased energy of Complex I\u2013II. In AD males, both NR treatment and dietary ketosis restored the \u0394\n G<\/jats:italic>\n \u2032 of Complex I\u2013II, where the ratio of the CoQ\/CoQH\n 2<\/jats:sub>\n couple was oxidized and the [NAD\n ox<\/jats:sub>\n ]\/[NADH\n red<\/jats:sub>\n ] couple was reduced. In AD females, only mice in the Ket diet group had a sufficiently reduced [NAD\n ox<\/jats:sub>\n ]\/[NADH\n red<\/jats:sub>\n ] couple to restore the free energy profile.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>","DOI":"10.1111\/jnc.16295","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T21:53:51Z","timestamp":1736459631000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Effect of Dietary Ketosis and Nicotinamide Riboside on Hippocampal Krebs Cycle Intermediates and Mitochondrial Energetics in a\n DNA<\/scp>\n Repair\u2010Deficient\n 3xTg<\/scp>\n \/\n POL\u03b2<\/scp>\n +\/\u2212<\/sup>\n Alzheimer Disease Mouse Model"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3075-7481","authenticated-orcid":false,"given":"Robert","family":"Pawlosky","sequence":"first","affiliation":[{"name":"Laboratory of Metabolic Control, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler G.","family":"Demarest","sequence":"additional","affiliation":[{"name":"The Laboratory of Molecular Gerontology, National Institute on Aging National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Todd","family":"King","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolic Control, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darlene","family":"Estrada","sequence":"additional","affiliation":[{"name":"The Laboratory of Molecular Gerontology, National Institute on Aging National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Veech","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolic Control, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilhelm A.","family":"Bohr","sequence":"additional","affiliation":[{"name":"The Laboratory of Molecular Gerontology, National Institute on Aging National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp105723r"},{"key":"e_1_2_12_3_1","first-page":"568","article-title":"Positron Emission Tomographic Studies of Aging and Alzheimer Disease","volume":"4","author":"Leon M. 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