The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
Microglia Drive Pockets of Neuroinflammation in Middle Age
Open accessPublished version of a preprint
Abstract
During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging. SIGNIFICANCE STATEMENT Microglia are CNS cells that are equipped to regulate neuronal health and function throughout the lifespan. We reveal that microglia in select brain regions begin to proliferate and produce inflammatory factors in late middle age, months before microglia in other brain regions. These findings demonstrate that CNS neuroinflammation during aging is not uniform. Moreover, they raise the possibility that local microglial responses to aging play a critical role in determining which populations of neurons are most vulnerable to functional decline and neurodegenerative disease.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Emerging evidence suggests that cardiovascular pathologies and atherosclerosis exacerbated by CH mutation-afflicted MoMF involve distinct effector molecules, such as Il1b and IL6.
“Emerging evidence suggests that cardiovascular pathologies and atherosclerosis exacerbated by CH mutation-afflicted MoM F involve distinct effector molecules, such as Il1 b and IL6 31,74 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [74]
The Results (pp. 13–15) discuss IL-1β and IL-6 in aging mouse brain tissue and serum, not cardiovascular disease. Searches for clonal hematopoiesis, mutation-afflicted monocyte-derived macrophages, and atherosclerosis found no passage linking those conditions to the cytokines. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343
Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Walker, A. J., Segel, M., Nemesh, J., Saunders, A., et al. (2018) · doi:10.1101/406140 · Cited by 2,225
Elmore, M. R. P., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.040 · Cited by 1,968
Gene regulation and DNA damage in the ageing human brain
Lu, T., Pan, Y., Kao, S.-Y., Li, C., Kohane, I., Chan, J., & Yankner, B. A. (2004) · Nature · doi:10.1038/nature02661 · Cited by 1,874
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858
Microglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710
Neuroinflammation: The Devil Is in the Details
DiSabato, D. J., Quan, N., & Godbout, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13607 · Cited by 1,640
Control of microglial neurotoxicity by the fractalkine receptor
Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1715 · Cited by 1,531
Normal aging induces A1-like astrocyte reactivity
Clarke, L. E., Liddelow, S. A., Chakraborty, C., Münch, A. E., Heiman, M., & Barres, B. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1800165115 · Cited by 1,237
Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases
Soto, C., & Pritzkow, S. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0235-9 · Cited by 1,180
Sala Frigerio, C., Wolfs, L., Fattorelli, N., Thrupp, N., Voytyuk, I., Schmidt, I., Mancuso, R., Chen, W.-T., Woodbury, M. E., Srivastava, G., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.099 · Cited by 926
Origin and differentiation of microglia
Ginhoux, F., Lim, S., Hoeffel, G., Low, D., & Huber, T. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00045 · Cited by 905
Microglia monitor and protect neuronal function through specialized somatic purinergic junctions
Cserép, C., Pósfai, B., Lénárt, N., Fekete, R., László, Z. I., Lele, Z., Orsolits, B., Molnár, G., Heindl, S., Schwarcz, A. D., et al. (2020) · Science · doi:10.1126/science.aax6752 · Cited by 684
Age-related myelin degradation burdens the clearance function of microglia during aging
Safaiyan, S., Kannaiyan, N., Snaidero, N., Brioschi, S., Biber, K., Yona, S., Edinger, A. L., Jung, S., Rossner, M. J., & Simons, M. (2016) · Nature Neuroscience · doi:10.1038/nn.4325 · Cited by 604
Selective vulnerability in neurodegenerative diseases
Fu, H., Hardy, J., & Duff, K. E. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0221-2 · Cited by 585
Huang, Y., Xu, Z., Xiong, S., Sun, F., Qin, G., Hu, G., Wang, J., Zhao, L., Liang, Y.-X., Wu, T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0090-8 · Cited by 560
Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration
Choi, I., Zhang, Y., Seegobin, S. P., Pruvost, M., Wang, Q., Purtell, K., Zhang, B., & Yue, Z. (2020) · Nature Communications · doi:10.1038/s41467-020-15119-w · Cited by 549
Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532
Epigenetic regulation of brain region-specific microglia clearance activity
Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh, Y.-H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0192-3 · Cited by 460
A Dramatic Increase of C1q Protein in the CNS during Normal Aging
Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., Kim, L., Tsai, H.-H., Huang, E. J., Rowitch, D. H., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1333-13.2013 · Cited by 423
Bäckman, L., Lindenberger, U., Li, S.-C., & Nyberg, L. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.12.008 · Cited by 414
Norden, D. M., Muccigrosso, M. M., & Godbout, J. P. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.10.028 · Cited by 413
Elmore, M. R. P., Hohsfield, L. A., Kramár, E. A., Soreq, L., Lee, R. J., Pham, S. T., Najafi, A. R., Spangenberg, E. E., Wood, M. A., West, B. L., et al. (2018) · Aging Cell · doi:10.1111/acel.12832 · Cited by 380
Scheiblich, H., Dansokho, C., Mercan, D., Schmidt, S. V., Bousset, L., Wischhof, L., Eikens, F., Odainic, A., Spitzer, J., Griep, A., et al. (2021) · Cell · doi:10.1016/j.cell.2021.09.007 · Cited by 360
Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices
Tremblay, M., Zettel, M. L., Ison, J. R., Allen, P. D., & Majewska, A. K. (2012) · Glia · doi:10.1002/glia.22287 · Cited by 309
VanRyzin, J. W., Marquardt, A. E., Argue, K. J., Vecchiarelli, H. A., Ashton, S. E., Arambula, S. E., Hill, M. N., & McCarthy, M. M. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.006 · Cited by 272
Modulating neurotoxicity through CX3CL1/CX3CR1 signaling
Limatola, C., & Ransohoff, R. M. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00229 · Cited by 210
Environment matters: microglia function and dysfunction in a changing world
Hanamsagar, R., & Bilbo, S. D. (2017) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.10.007 · Cited by 122
Cx3cr1- deficient microglia exhibit a premature aging transcriptome
Gyoneva, S., Hosur, R., Gosselin, D., Zhang, B., Ouyang, Z., Cotleur, A. C., Peterson, M., Allaire, N., Challa, R., Cullen, P., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900453 · Cited by 103
Primiani, C. T., Ryan, V. H., Rao, J. S., Cam, M. C., Ahn, K., Modi, H. R., & Rapoport, S. I. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110972 · Cited by 56
Flagged first, then by citations
Research works printed but not linked: 62
- 10.1038/s41586-020-2777-8 · DOI · Paper page
- 10.1038/s41580-019-0185-4 · DOI · Paper page
- 10.1007/s00702-017-1795-7 · DOI
- 10.1016/j.conb.2011.01.002 · DOI · Paper page
- 10.1111/nan.12297 · DOI
- 10.1016/j.celrep.2017.12.039 · DOI · Paper page
- 10.3389/fnana.2014.00152 · DOI
- 10.1038/nrn1809 · DOI
- 10.7554/eLife.57495 · DOI
- 10.1002/ana.20682 · DOI
- 10.1038/nn.3364 · DOI
- 10.1002/glia.22350 · DOI · Paper page
- 10.1111/j.1474-9726.2010.00660.x · DOI · Paper page
- 10.1111/tra.12714 · DOI
- 10.1016/j.neuron.2017.06.020 · DOI · Paper page
- 10.1002/glia.20663 · DOI
- 10.1186/1742-2094-4-9 · DOI
- 10.1212/WNL.0b013e3181d5a4a3 · DOI
- 10.1038/nn.4222 · DOI · Paper page
- 10.1038/s41593-019-0419-y · DOI
- 10.1016/j.immuni.2018.11.004 · DOI · Paper page
- 10.1016/j.bbi.2011.11.006 · DOI · Paper page
- 10.4172/2329-6895.1000120 · DOI
- 10.1111/acel.12149 · DOI · Paper page
- 10.3389/fncel.2020.565841 · DOI
- 10.1111/ejn.14740 · DOI
- 10.1111/jnc.12477 · DOI
- 10.1016/j.nlm.2014.11.009 · DOI
- Ikeda-Matsuo, 2021, Microsomal prostaglandin E synthase-1 induced by hemoglobin in microglia contributes to inflammation and neuronal death, Proc Annu Meet Japanese Pharmacol Soc, 94, 1
- Kennedy RH , Silver R (2015) Neuroimmune signaling: cytokines and the CNS. In: Neuroscience in the 21st Century. New York:Springer. · DOI
- Kierdorf, 2017, Microglia in steady state, J Clin Invest, 127, 2301, 10.1172/JCI90602 · DOI
- 10.1038/s41467-018-06118-z · DOI
- 10.3389/fncel.2018.00282 · DOI
- 10.1523/JNEUROSCI.1268-12.2013 · DOI · Paper page
- 10.1016/j.nbd.2018.05.015 · DOI
- 10.1016/j.neuron.2009.08.039 · DOI · Paper page
- 10.1212/WNL.47.2.425 · DOI · Paper page
- 10.1038/nrn.2016.165 · DOI · Paper page
- 10.1038/nrn3200 · DOI · Paper page
- Naito, 1989, Ultrastructural behavior of human immunodeficiency virus (HIV) in multinucleated giant cells in the brain of a Japanese hemophiliac presenting AIDS encephalopathy, Ultrastruct Pathol, 13, 433, 10.3109/01913128909048493 · DOI
- 10.1186/s13041-020-00585-6 · DOI
- 10.1016/j.immuni.2019.02.007 · DOI · Paper page
- 10.1186/s40478-018-0636-8 · DOI
- 10.1016/j.neurobiolaging.2013.07.008 · DOI
- 10.1016/j.cytogfr.2017.03.005 · DOI
- 10.1016/j.neuron.2021.01.027 · DOI · Paper page
- 10.1016/j.nbd.2020.105008 · DOI
- 10.1038/nm.4397 · DOI · Paper page
- 10.1016/j.expneurol.2014.04.032 · DOI
- 10.1002/glia.23834 · DOI
- 10.1007/s00441-012-1537-y · DOI · Paper page
- 10.1186/s13041-016-0191-9 · DOI
- 10.1097/00005072-199909000-00006 · DOI
- 10.3389/fnagi.2017.00194 · DOI
- 10.1002/dneu.22572 · DOI · Paper page
- 10.1002/jbt.21464 · DOI
- 10.1016/j.tins.2020.01.003 · DOI · Paper page
- 10.1155/NP.2005.161 · DOI
- 10.1212/WNL.0000000000007094 · DOI · Paper page
- 10.1146/annurev-physiol-022516-034406 · DOI · Paper page
- 10.1136/jnnp.2003.020982 · DOI
- 10.1146/annurev-physiol-021014-071649 · DOI
Cited by
Sorted by citations
Kim, J.-S., Trzebanski, S., Shin, S.-H., Schori, L., Frumer Friedman, G. R., Ilani, N. C., Kadam, A., Vicario, R., Aust, O., Bugaeva, P., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115609 · Cited by 33
Metadata
- Authors
- Moca, E. N., Lecca, D., Hope, K. T., Etienne, F., Schaler, A. W., Espinoza, K., Chappell, M. S., Gray, D. T., Tweedie, D., Sidhu, S., Masukawa, L., Sitoy, H., Mathew, R., Saban, D. R., Greig, N. H., & De Biase, L. M.
- Affiliations
- University of California, Los Angeles (US)
- National Institute on Aging (US)
- Duke University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2022-04-08
- Volume
- 42
- Issue
- 19
- Pages
- 3896-3918
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC9097782
- OpenAlex
- W4226190883
- Cited by
- 42
- References
- 31
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 11 · 2023: 9 · 2022: 5
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- American Federation on Aging Research (A19090)
- David Geffen School of Medicine at UCLA (Start-up Funds)
- HHS | NIH | National Institute on Aging (Intramural Research Program)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- microglial aging, neuroinflammation, middle age (human life stage), basal ganglia, ventral tegmental area, substantia nigra pars compacta, microglial proliferation, CX3CR1, microglial heterogeneity, synaptic function, neurodegeneration
- MeSH terms
- Neuroinflammatory Diseases, Animals, Female, Male, Neurons, Synapses, Microglia, Neurodegenerative Diseases, Mice
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
