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Borkowski, K.* ; Liang, N.* ; Zhao, N.* ; Arnold, M. ; Huynh, K.* ; Karu, N.* ; MahmoudianDehkordi, S.* ; Kueider-Paisley, A.* ; Kanekiyo, T.* ; Bu, G.* ; Kaddurah-Daouk, R.*

APOE genotype influences on the brain metabolome of aging mice - role for mitochondrial energetics in mechanisms of resilience in APOE2 genotype.

Mol. Neurodegener. 20:97 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
UNLABELLED: Alzheimer’s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00888-z.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Apolipoprotein-e Genotype; Alzheimers-disease Brain; Chain Amino-acids; Cognitive Decline; Association; Serotonin; Mouse; Age; Model; Biomarkers
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
e-ISSN 1750-1326
Zeitschrift Molecular Neurodegeneration
Quellenangaben Band: 20, Heft: 1, Seiten: , Artikelnummer: 97 Supplement: ,
Verlag BioMed Central
Verlagsort Campus, 4 Crinan St, London N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503891-001
Förderungen National Institute on Aging
DOI 10.1186/s13024-025-00888-z
WOS ID 001562107500001
Scopus ID 105015776316
PubMed ID 40898377
Erfassungsdatum 2025-11-13
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