Cited by 26Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging

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Cleland, Nicholas R.W., Potter, Garrett J., Buck, Courtney, Quang, Daphne, Oldham, Dean, Neal, Mikaela, Saviola, Anthony, Niemeyer, Christy S. +2 more·2024·Brain Research

Published version of a preprint

Abstract

Despite Alzheimer's disease (AD) disproportionately affecting women, the mechanisms remain elusive. In AD, microglia undergo 'metabolic reprogramming', which contributes to microglial dysfunction and AD pathology. However, how sex and age contribute to metabolic reprogramming in microglia is understudied. Here, we use metabolic imaging, transcriptomics, and metabolic assays to probe age- and sex-associated changes in brain and microglial metabolism. Glycolytic and oxidative metabolism in the whole brain was determined using Fluorescence Lifetime Imaging Microscopy (FLIM). Young female brains appeared less glycolytic than male brains, but with aging, the female brain became 'male-like.' Transcriptomic analysis revealed increased expression of disease-associated microglia (DAM) genes (e.g., ApoE, Trem2, LPL), and genes involved in glycolysis and oxidative metabolism in microglia from aged females compared to males. To determine whether estrogen can alter the expression of these genes, BV-2 microglia-like cell lines, which abundantly express DAM genes, were supplemented with 17β-estradiol (E2). E2 supplementation resulted in reduced expression of DAM genes, reduced lipid and cholesterol transport, and substrate-dependent changes in glycolysis and oxidative metabolism. Consistent with the notion that E2 may suppress DAM-associated factors, LPL activity was elevated in the brains of aged female mice. Similarly, DAM gene and protein expression was higher in monocyte-derived microglia-like (MDMi) cells derived from middle-aged females compared to age-matched males and was responsive to E2 supplementation. FLIM analysis of MDMi from young and middle-aged females revealed reduced oxidative metabolism and FAD+ with age. Overall, our findings show that altered metabolism defines age-associated changes in female microglia and suggest that estrogen may inhibit the expression and activity of DAM-associated factors, which may contribute to increased AD risk, especially in post-menopausal women.

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  1. Pedersen SB,, 1991. Nuclear estradiol binding in rat adipocytes. Regional variations and regulatory influences of hormones. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1093, 80– 86. 1646650

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Authors
Cleland, N. R. W., Potter, G. J., Buck, C., Quang, D., Oldham, D., Neal, M., Saviola, A., Niemeyer, C. S., Dobrinskikh, E., & Bruce, K. D.
Affiliations
University of Colorado Anschutz (US)
Corresponding author
Bruce, Kimberley D.
Venue
Brain Research
Publisher
Elsevier BV
Published
2024-04
Volume
1829
Pages
148772
ISSN
0006-8993 (ISSN-L)
OpenAlex
W4390969423
Cited by
26
References
141
Citations by year
2026: 13 · 2025: 8 · 2024: 5
FWCI
2.68
Type
journal article
Language
en
Open access
Locations
  • Brain Research (acceptedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (R01AG079217-02)
  • CU Anschutz Ludeman Family Center for Women's Health Research
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, sex differences, brain aging, microglial metabolism, disease-associated microglia, metabolic reprogramming, glycolysis, oxidative metabolism, estradiol, estrogen, apolipoprotein E, TREM2, lipoprotein lipase, postmenopausal women

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