Su W, Saravia J, Risch I, Rankin S, Guy C, Chapman NM, Shi H, Sun Y, Kc A, Li W, Huang H, Lim SA, Hu H, Wang Y, Liu D, Jiao Y, Chen PC, Soliman H, Yan KK, Zhang J, Vogel P, Liu X, Serrano GE, Beach TG, Yu J, Peng J, Chi H. CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology. Nat Immunol. 2023 Oct;24(10):1735-1747. Epub 2023 Sep 7 PubMed.
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Brigham and Women's Hospital/Harvard Medical School
This paper is interesting. In our Krasemann 2017 dataset, plaque-associated microglia induce CXCL16, in line with the results reported here.
This study shows that CD8 T cells are recruited via the microglial CXCL16–CCR6 axis and enter the AD brain to suppress inflammatory microglia. At first glance, this contradicts the idea that MGnD microglia are beneficial. But it's all about timing. As shown in Fig. 1e, CD8 infiltration in the 5xFAD model occurs quite late, around nine to 12 months. By this point, microglia are likely chronically activated and functionally exhausted. In this context, the induction of CXCL16 might reflect a “help needed” signal, with microglia recruiting CD8 T cells in an attempt to reset or dampen their overactivation (“too much love will kill you”).
This fits with the emerging concept of stage-dependent intervention:
Importantly, our Science Translational Medicine paper using Xenon gas (Brandao et al., 2025) provides direct evidence that Clec7a⁺ MGnD microglia are protective in AD mice. When we ablated this subset at an early disease stage (four months), disease progression worsened, strongly supporting the beneficial role of MGnD microglia when activated at the right time.
References:
Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017 Sep 19;47(3):566-581.e9. PubMed.
Brandao W, Jain N, Yin Z, Kleemann KL, Carpenter M, Bao X, Serrano JR, Tycksen E, Durao A, Barry JL, Baufeld C, Guneykaya D, Zhang X, Litvinchuk A, Jiang H, Rosenzweig N, Pitts KM, Aronchik M, Yahya T, Cao T, Takahashi MK, Krishnan R, Davtyan H, Ulrich JD, Blurton-Jones M, Ilin I, Weiner HL, Holtzman DM, Butovsky O. Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy. Sci Transl Med. 2025 Jan 15;17(781):eadk3690. Epub 2025 Jan 15 PubMed.
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