Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging
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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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Female microglia upregulate genes related to metabolic activities like glycolysis and oxidative metabolism, which become more pronounced with aging.
“female microglia upregulate genes related to metabolic activities like glycolysis and oxidative metabolism, which become more pronounced with aging.69”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [69]
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Lipoprotein Lipase and Its Delivery of Fatty Acids to the Heart
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Patient-Derived In Vitro Models of Microglial Function and Synaptic Engulfment in Schizophrenia
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Self-citationHeterogeneous Pulmonary Response After Tracheal Occlusion: Clues to Fetal Lung Growth
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Self-citationFunctional Analysis of a Novel Immortalized Murine Microglia Cell Line in 3D Spheroid Model
Angst, G., Tang, X., & Wang, C. (2023) · Neurochemical Research · doi:10.1007/s11064-023-03952-6 · Cited by 3 · see citing works
Flagged first, then by citations
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Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.029 · Cited by 104 · see citing works
Lipid and lipoprotein metabolism in microglia: Alzheimer’s disease mechanisms and interventions
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Do microglia metabolize fructose in Alzheimer’s disease?
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Self-citationMetabolic and inflammatory roles of glial cells in neurodegenerative and cerebrovascular diseases
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GPR34 regulates microglia state and loss-of-function rescues TREM2 metabolic dysfunctionPreprint
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Castro‐Aldrete, L., Einsiedler, M., Cuní‐López, C., Vanhaelen, Q., Silvestri, A., Ferretti, M. T., de Gennaro, M. E., Putignano, G., Guix, M., Marino, N., et al. (2025) · Nature Reviews Bioengineering · doi:10.1038/s44222-025-00355-w · Cited by 4 · see citing works
Impact of wildfire smoke and diesel exhaust on inflammatory response in aging human microgliaPreprint
Cuní‐López, C., Ng, M. F., Stewart, R., Milton, L. A., Etebar, F., Sun, Y., Vivian, E. R., Nguyen, T. H., Asare, P. F., Lupton, M. K., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.20.629570 · Cited by 4 · see citing works
Fueling Alzheimer’s Disease: Where Does Immunometabolism Stand?
Correia, S. C., Perry, G. L., & Moreira, P. I. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240787 · Cited by 3 · see citing works
Guo, W., Wu, Y., Zhao, S., & Xu, J. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1627414 · Cited by 3 · see citing works
Li, Y., Lu, W., Qian, W., Liao, X., Wang, P., Wang, Y., Jiao, W., Wang, M., Zhao, J., Yang, J., et al. (2026) · Nutrients · doi:10.3390/nu18020315 · Cited by 3 · see citing works
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Inflammaging and the sex-frailty paradox
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The Double Face of Microglia in the Brain
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Intranasal HSV‑1 infection drives region‑specific interferon‑dominant microglial remodeling
Frietze, S. E., Lunn, C., Oldham, D., Boyd, J. R., Bubak, A. N., Bustillos, A., Nagel, M. A., Restrepo, D., Bruce, K. D., & Niemeyer, C. S. (2026) · PLoS Pathogens · doi:10.1371/journal.ppat.1014684 · Cited by 1 · see citing works
Self-citationMicroglial response to amyloid-β pathology is modulated by X chromosome dosagePreprint
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Research advances on estrogen deficiency leading to depression
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Fibrinogen as a Driver of Oxidative Stress and Apoptosis in the Fetal Brain After Maternal InfluenzaPreprint
Gonzalez-Ricon, R., Rigal, F. J., Chalen, I., & Antonson, A. M. (2026) · Research Square · doi:10.21203/rs.3.rs-10396951/v1
Kang, S., & Goodridge, H. S. (2026) · Aging Cell · doi:10.1111/acel.70660
Vallés, A. S., & Barrantes, F. J. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2026.1860052
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Chen, Y., Li, F., Junlei, Z., 魏明清, 倪敬年, Li, T., Yao, L., Tian, J., & Shi, J. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71909
- 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.
- ORCID
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2024-04
- Volume
- 1829
- Pages
- 148772
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC12036313
- 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
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 319 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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