Choi I, Wang M, Yoo S, Xu P, Seegobin SP, Li X, Han X, Wang Q, Peng J, Zhang B, Yue Z. Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence. Nat Cell Biol. 2023 Jul;25(7):963-974. Epub 2023 May 25 PubMed.

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  1. This interesting study from Dr. Yue’s group reveals the novel autophagy-mediated regulatory mechanism of disease-associated/neurodegenerative microglia (DAM/MGnD) phenotype induction (Krasemann et al., 2017) via microglia-specific targeting of Atg7. I am intrigued that autophagosomal machinery may regulate microglial activation, because we recently observed that deletion from microglia of tumor susceptibility gene Tsg101, one of the ESCRT1 (endosomal sorting complex required for transport) molecules, downregulated DAM/MGnD induction in PS19 mice (Apr 2023 news). Interestingly, we found the Tsg101 cKO-microglia significantly suppressed phagocytic function in vitro, which could lead the suppression of DAM/MGnD in PS19 mice since phagocytosis of dead neurons is an established method for the induction of this phenotype (Krasemann et al., 2017). While the authors showed that microglial deletion of Atg7, a critical molecule for the autophagosome machinery, in 5XFAD mice downregulated DAM/MGnD signature genes, they did not examine phagocytic function in Atg7cKO microglia. We may expect similar results since phagocytosis and autophagy share molecular pathways for evolutionally conserved functions in myeloid cells (Eshraghi et al., 2021). Indeed, Atg7 activation recruits LC3, beclin, and other phagocytosis-related molecules to the phagosome membranes. Thus, it is possible that Atg7 cKO downregulates DAM/MGnD induction via suppression of microglial phagocytosis.

    The authors also suspect that senescence triggered by autophagy dysfunction could be the mechanism that explains the downregulation of DAM. However, DAM/MGnD genes, such as APOE, Cst7, and CD74, are upregulated as well as the senescence gene Cdkn1a, in Atg7cKO microglia, according to their single RNA-Seq analysis. Indeed, the Gomez-Nicola group recently reported positive correlation between microglial senescence and DAM/MGnD induction (Hu et al., 2021). Thus, the regulation of DAM/MGnD induction by senescence may be context-dependent (presence or absence of disease status), and this finding needs more validation with senescence-specific targeting approaches.

    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.

    Eshraghi M, Adlimoghaddam A, Mahmoodzadeh A, Sharifzad F, Yasavoli-Sharahi H, Lorzadeh S, Albensi BC, Ghavami S. Alzheimer's Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia. Int J Mol Sci. 2021 Mar 24;22(7) PubMed.

    Hu Y, Fryatt GL, Ghorbani M, Obst J, Menassa DA, Martin-Estebane M, Muntslag TA, Olmos-Alonso A, Guerrero-Carrasco M, Thomas D, Cragg MS, Gomez-Nicola D. Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology. Cell Rep. 2021 Jun 8;35(10):109228. PubMed.

    View all comments by Seiko Ikezu

  2. In this paper, inhibition of microglial autophagy induced senescence, suppressed disease-associated microglia, impaired engagement with Aβ plaques, and aggravated neuropathology. The senolytic drugs dasatinib and quercetin removed senescent microglia, restored DAMs and homeostasis of Aβ plaques, and reduced neuropathology. It is interesting to link microglial autophagy and senescence with Aβ plaque regulation and AD pathogenesis.

    Previous research has interpreted DAMs as a toxic contributor to AD, which has led to therapeutic strategies aimed at calming DAMs. However, this paper provides new insight into the possibility that DAMs are actually functioning microglia that reduce AD pathology, and that senescent and nonfunctioning microglia are the ones that aggravate AD pathology. This may suggest a new therapeutic strategy of enhancing young DAMs and removing senescent microglia.

    However, it is not yet clear whether DAMs are beneficial or harmful. It is possible that their role may differ depending on the stage and environment. Microglia may change from normal active microglia to hyper-immune and inflammatory, and then to senescent and degenerating microglia, over the long duration of aging and AD. More research is needed to fully understand the role of microglia in AD and to develop effective therapeutic strategies.

    Overall, this study provides valuable new insights into the role of microglia in AD and suggests that senolytic drugs may be a potential treatment for the disease. However, more research is needed to confirm these findings and to develop effective therapeutic strategies.

    View all comments by Seung-Yong Yoon

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  1. When Autophagy Stops, Microglia Sour into Senescence