{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:38:20Z","timestamp":1790775500154,"version":"4.1.0"},"reference-count":238,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T00:00:00Z","timestamp":1702339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo Beneficenza Intesa San Paolo","award":["B-2022-0094"],"award-info":[{"award-number":["B-2022-0094"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the \u201csentinels\u201d of internal and external perturbations and have long lifespans. We aim to emphasize microglial signatures in physiologic brain aging and Alzheimer\u2019s disease (AD). A systematic literature search of all published articles about microglial senescence in human healthy aging and AD was performed, searching for PubMed and Scopus online databases. Among 1947 articles screened, a total of 289 articles were assessed for full-text eligibility. Microglial transcriptomic, phenotypic, and neuropathological profiles were analyzed comprising healthy aging and AD. Our review highlights that studies on animal models only partially clarify what happens in humans. Human and mice microglia are hugely heterogeneous. Like a two-sided coin, microglia can be protective or harmful, depending on the context. Brain health depends upon a balance between the actions and reactions of microglia maintaining brain homeostasis in cooperation with other cell types (especially astrocytes and oligodendrocytes). During aging, accumulating oxidative stress and mitochondrial dysfunction weaken microglia leading to dystrophic\/senescent, otherwise over-reactive, phenotype-enhancing neurodegenerative phenomena. Microglia are crucial for managing A\u03b2, pTAU, and damaged synapses, being pivotal in AD pathogenesis.<\/jats:p>","DOI":"10.3390\/cells12242824","type":"journal-article","created":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T09:15:33Z","timestamp":1702372533000},"page":"2824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Microglial Senescence and Activation in Healthy Aging and Alzheimer\u2019s Disease: Systematic Review and Neuropathological Scoring"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9691-0890","authenticated-orcid":false,"given":"Antonio","family":"Malvaso","sequence":"first","affiliation":[{"name":"IRCCS \u201cC. Mondino\u201d Foundation, National Neurological Institute, Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Gatti","sequence":"additional","affiliation":[{"name":"IRCCS \u201cC. Mondino\u201d Foundation, National Neurological Institute, Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4000-786X","authenticated-orcid":false,"given":"Giulia","family":"Negro","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Milano Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Calatozzolo","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Medici","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8463-6879","authenticated-orcid":false,"given":"Tino Emanuele","family":"Poloni","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3389\/fncel.2013.00045","article-title":"Origin and differentiation of microglia","volume":"7","author":"Ginhoux","year":"2013","journal-title":"Front. 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