{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:20:01Z","timestamp":1787505601326,"version":"build-2736575974"},"reference-count":118,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"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. Aging Neurosci."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is characterized by amyloid-beta (A\u03b2) deposition, tau hyperphosphorylation, and chronic neuroinflammation. Emerging evidence from preclinical models suggests that aberrant immune crosstalk between regulatory T cells (Tregs) and microglia may contribute to disease progression, though its precise role in human AD remains to be fully elucidated. In rodent models, Tregs have been shown to cross the blood-brain barrier and, through cell-contact-dependent mechanisms and secretion of pro-resolutive factors such as transforming growth factor-\u03b2, appear to promote microglial transitions toward pro-resolutive states and facilitate A\u03b2 phagocytosis. However, these mechanisms have been predominantly demonstrated in transgenic mouse strains with early-onset amyloid pathology, and their relevance to the slow, aging-associated progression of human sporadic AD requires cautious interpretation. In AD animal models, reductions in Treg numbers and suppressive function coincide with microglial dysregulation, with the interaction between these cell types shifting from homeostatic to pro-inflammatory states as pathology advances. It is critical to note that while such findings suggest a potential regulatory axis, they derive largely from simplified animal systems that do not fully recapitulate human immune aging, genetic heterogeneity, or decades-long disease kinetics. Moreover, therapeutic strategies targeting this crosstalk that show efficacy in mice have yielded inconsistent results in early human trials, highlighting significant translational gaps. This review critically assesses the current preclinical evidence, emphasizing that findings from rodent models should be interpreted as hypothesis-generating rather than definitive proof of mechanism in human disease. We underscore the urgent need for validation through human tissue analysis, cerebrospinal fluid biomarkers, and advanced humanized model systems before Treg-microglia interactions can be established as robust therapeutic targets for AD.<\/jats:p>","DOI":"10.3389\/fnagi.2026.1838306","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:04:12Z","timestamp":1779689052000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Treg\u2013microglia crosstalk in Alzheimer\u2019s disease: stage-dependent dynamics, molecular mechanisms, and translational challenge"],"prefix":"10.3389","volume":"18","author":[{"given":"Hua","family":"Fu","sequence":"first","affiliation":[{"name":"The Second Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin","place":["Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin","place":["Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin","place":["Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"fcaf092","DOI":"10.1093\/braincomms\/fcaf092","article-title":"Could immunotherapy and regulatory T cells be used therapeutically to slow the progression of Alzheimer\u2019s disease?","volume":"7","author":"Abbott","year":"2025","journal-title":"Brain Commun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.neuron.2017.03.042","article-title":"iPSC-derived human microglia-like cells to study neurological diseases.","volume":"94","author":"Abud","year":"2017","journal-title":"Neuron"},{"key":"B3","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.cmet.2020.07.001","article-title":"Mitochondrial oxidative damage underlies regulatory T cell defects in autoimmunity.","volume":"32","author":"Alissafi","year":"2020","journal-title":"Cell Metab."},{"key":"B4","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1093\/brain\/aww330","article-title":"Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer\u2019s disease mice.","volume":"140","author":"Alves","year":"2017","journal-title":"Brain: J. 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