{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T12:25:03Z","timestamp":1787228703882,"version":"build-2736575974"},"reference-count":189,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Alzheimer\u2019s disease is a complex neurodegenerative disorder characterized pathologically by amyloid-\u03b2 deposition and pathological tau aggregation. Amyloid-\u03b2 deposition typically occurs during the preclinical stage; however, amyloid burden does not exhibit a simple linear relationship with neurodegeneration or cognitive decline. In contrast, the spatial distribution of tau pathology is more closely associated with clinical progression. As the resident innate immune cells of the central nervous system, microglia participate in the recognition, uptake, and containment of amyloid-\u03b2 and tau. Nevertheless, persistent exposure to damage-associated signals can lead to lysosomal dysfunction, dysregulated lipid metabolism, and mitochondrial impairment in microglia, thereby amplifying neuroinflammation, aberrant synaptic elimination, and neuronal injury. The traditional binary M1\/M2 classification is inadequate to capture the continuous, overlapping, and context-dependent functional states of microglia, which vary across brain regions, genetic backgrounds, and disease stages. This review integrates recent evidence from genetic, single-cell\/single-nucleus, and spatial transcriptomic studies and proposes a \u201ccellular state\u2013pathological network\u2013therapeutic window\u201d framework. We systematically discuss the roles of microglia in amyloid-\u03b2 plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA\u2013cGAS\u2013STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia\u2013tau feedback. On this basis, we critically evaluate the mechanistic rationale, stage dependence, and translational limitations of therapeutic axes involving TREM2\/CD33, P2X7\u2013NLRP3 and cGAS\u2013STING, CSF1R\/complement, and TNF\u2013TNFR1\u2013RIPK1. Current evidence suggests that the key to microglia-targeted therapy is not the broad activation or suppression of immune responses, but rather the biomarker-guided and disease-stage-specific modulation of pathogenic signaling while preserving homeostatic functions such as plaque containment, debris clearance, synaptic maintenance, and tissue repair.<\/jats:p>","DOI":"10.3389\/fncel.2026.1902577","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:44:51Z","timestamp":1787226291000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Microglia-mediated neuroinflammation in Alzheimer\u2019s disease: mechanisms and emerging therapeutic targets"],"prefix":"10.3389","volume":"20","author":[{"given":"Lianjing","family":"Xu","sequence":"first","affiliation":[{"name":"Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jiang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Feng","family":"Xing","sequence":"additional","affiliation":[{"name":"School of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianye","family":"Lan","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Ta","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.molcel.2018.01.027","article-title":"Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2.","volume":"69","author":"Annibaldi","year":"2018","journal-title":"Mol. 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