Intrinsic aerobic capacity modulates Alzheimer's disease pathological hallmarks, brain mitochondrial function and proteome during aging.

Autor: Kugler BA; University of Kansas Medical Center Department of Cell Biology and Physiology and Internal Medicine, Kansas City, KS, USA., Lysaker CR; University of Kansas Alzheimer's Disease Center and Department of Neurology, Kansas City, KS, USA., Franczak E; University of Kansas Medical Center Department of Cell Biology and Physiology and Internal Medicine, Kansas City, KS, USA., Hauger BM; University of Kansas Alzheimer's Disease Center and Department of Neurology, Kansas City, KS, USA., Csikos V; University of Kansas Alzheimer's Disease Center and Department of Neurology, Kansas City, KS, USA., Stopperan JA; University of Kansas Alzheimer's Disease Center and Department of Neurology, Kansas City, KS, USA., Allen JA; University of Kansas Medical Center Department of Cell Biology and Physiology and Internal Medicine, Kansas City, KS, USA., Stanford JA; University of Kansas Medical Center Department of Cell Biology and Physiology and Internal Medicine, Kansas City, KS, USA., Koch LG; Department of Physiology and Pharmacology, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, USA., Britton SL; Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA., Thyfault JP; University of Kansas Alzheimer's Disease Center and Department of Neurology, Kansas City, KS, USA.; University of Kansas Medical Center Department of Cell Biology and Physiology and Internal Medicine, Kansas City, KS, USA.; Research Service, Kansas City VA Medical Center Department of Veterans Affairs, University of Kansas Diabetes Center, Kansas City, KS, USA.; University of Kansas Medical Center Department of Molecular Biology and Biochemistry, Kansas City, KS, USA., Wilkins HM; University of Kansas Alzheimer's Disease Center and Department of Neurology, Kansas City, KS, USA. hwilkins@kumc.edu.; University of Kansas Medical Center Department of Molecular Biology and Biochemistry, Kansas City, KS, USA. hwilkins@kumc.edu.; Department of Neurology University of Kansas Medical Center, Kansas City, KS, USA. hwilkins@kumc.edu.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2024 Oct; Vol. 46 (5), pp. 4955-4967. Date of Electronic Publication: 2024 Jun 13.
DOI: 10.1007/s11357-024-01248-3
Abstrakt: Low aerobic capacity is strongly associated with all-cause mortality and risk for Alzheimer's disease (AD). Individuals with early dementia and AD have lower aerobic capacity compared to age-matched controls. The mechanism by which aerobic capacity influences AD risk is unknown but is likely mediated by sexual dimorphism and tissue-level differences in mitochondrial energetics. Here, we used rats selectively bred for large differences in intrinsic aerobic exercise capacity. Brain tissue from 18-month and 24-month-old female and male low-capacity runner (LCR) and high-capacity runner (HCR) rats were analyzed for markers of mitochondrial function and AD-associated pathologies. LCR rats, irrespective of sex, exhibited a greater increase in brain amyloid beta (Aβ 42 ) and tau hyperphosphorylation (pTau thr181 /total tau) with aging. In female LCR rats, brain mitochondrial respiration at states 3, 4, and FCCP-induced uncoupling, when stimulated with pyruvate/malate, was reduced at 18 and 24 months, leading to lower ATP-linked mitochondrial respiration compared to mitochondria from HCR rats. Male LCR rats also showed reduced complex II-stimulated mitochondrial respiration (succinate + rotenone) at 24 months compared to HCR rats. Differences in mitochondrial respiration were associated with tau hyperphosphorylation and Aβ42 alterations in both HCR and LCR strains. Proteomic analysis unveiled a distinct difference in the mitochondrial proteome, wherein female LCR rats displayed diminished mitochondrial translation and oxidative phosphorylation (OXPHOS) proteins at 18 months compared to female HCR rats. Conversely, male LCR rats exhibited increased OXPHOS protein abundance but reduced tricarboxylic acid (TCA) cycle proteins compared to male HCR rats. These findings underscore a robust association between intrinsic aerobic exercise capacity, brain mitochondrial function, and AD pathologies during aging.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: