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.

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  1. This interesting study by Hu et al. presented two take-home messages.

    First, subpopulations of AD-reactive microglia are senescent. By studying the APP/PS1 mouse model, the authors showed that activated microglia proliferate around amyloid plaques, which is consistent with our previous findings (Wang et al., 2016), such that these plaque-associated microglia reach the Hayflick limit faster than others. In line with this, the authors identified overlaps between DAM and senescence signatures, although not complete, indicating subpopulations of DAM undergo senescence. Interestingly, senescence markers were also evident in microglia from human AD samples.

    Second, inhibition of microglia proliferation leads to reduced senescence in microglia, which ameliorates amyloid pathology in the APP/PS1 mouse model. The authors used a low dose of a CSF1R inhibitor that reduces microglia proliferation without killing the cells.

    This paper nicely raises interest in microglia senescence in AD, a topic that has not been adequately addressed so far. One question remains to be clarified: whether reduced amyloid pathology observed in APP/PS1 treated with a low dose of CSF1R inhibitor is due to reduced microglia senescence, in other words, “rejuvenation” of microglia, or simply reduction of microglia as such, since pre-plaque depletion of microglia by a high dose of CSF1R inhibitor has been shown to prevent plaque pathology (Sosna et al., 2018; Spangenberg et al., 2019). 

    We noticed that Trem2-/- 5XFAD microglia have a defect in proliferation and do not convert to DAM (Wang et al., 2015), likely preventing a senescence phenotype; yet Trem2-/- 5XFAD mice develop worse pathology and microglia in these mice are more apoptotic (Ulland et al., 2017). Could the senescence phenotype seen in AD microglia be a consequence of plaque deposition and not the cause? Further studies are needed to establish a causal relationship between microglia senescence and pathology.

    References:

    Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016 May 2;213(5):667-75. Epub 2016 Apr 18 PubMed.

    Sosna J, Philipp S, Albay R 3rd, Reyes-Ruiz JM, Baglietto-Vargas D, LaFerla FM, Glabe CG. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener. 2018 Mar 1;13(1):11. PubMed.

    Spangenberg E, Severson PL, Hohsfield LA, Crapser J, Zhang J, Burton EA, Zhang Y, Spevak W, Lin J, Phan NY, Habets G, Rymar A, Tsang G, Walters J, Nespi M, Singh P, Broome S, Ibrahim P, Zhang C, Bollag G, West BL, Green KN. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model. Nat Commun. 2019 Aug 21;10(1):3758. PubMed.

    Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Gilfillan S, Krishnan GM, Sudhakar S, Zinselmeyer BH, Holtzman DM, Cirrito JR, Colonna M. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015 Mar 12;160(6):1061-71. Epub 2015 Feb 26 PubMed.

    Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Zhou Y, Cairns NJ, Kambal A, Loginicheva E, Gilfillan S, Cella M, Virgin HW, Unanue ER, Wang Y, Artyomov MN, Holtzman DM, Colonna M. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017 Aug 10;170(4):649-663.e13. PubMed.

    View all comments by Yingyue Zhou

  2. One of the most important questions related to the role of DAM (MGnD) microglia is their contribution to plaque pathology and disease progression in AD. The study by Hu and colleagues is a valuable contribution to our understanding of the role of early developmental microglial changes in driving Aβ pathology and it validates the heterogeneity of DAM/MGnD microglial activation states.

    The authors raised the interesting idea that a high rate of microglia proliferation associated with Aβ-plaque and DAM signature results in telomere shortening and microglia senescence. The authors demonstrated that excessive microglia replication coincides with DAM phenotype in APP/PS1 mice. A significant fraction of DAM microglia displayed a senescent profile, which was investigated by also incorporating multiple other published datasets. In human AD, microglia showed no change in morphology, but strong senescent markers as compared to non-demented controls, confirming previous studies pioneered by Wolfgang Streit and others.

    To address their hypothesis, the authors used the CSF1R inhibitor GW2580 to suppress microglia proliferation. Previously, several labs had showed this specific CSF1R inhibitor did not deplete microglia but inhibited microglia proliferation. The authors concluded that the inhabitation of proliferative microglia attenuated the DAM phenotype and improved disease related to neuritic plaque pathology and protection of synapses. However, it is possible that this inhibitor may also deplete both microglia and macrophages at the same time (Chalmers et al., 2017). In addition, it is not clear whether this inhibitor may also reduce microglial migration toward plaque rather than inhibiting their proliferation. Also, the authors did not measure the effect of GW2580 treatment on telomere length, which would be required to validate their hypothesis.

    Thus, future studies using specific genetic and fate-map analysis approaches, and specific modulators targeting DAM/MGnD, are required in order to determine the contribution of this important phenotype to disease pathology.

    References:

    Chalmers SA, Wen J, Shum J, Doerner J, Herlitz L, Putterman C. CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus. Clin Immunol. 2017 Dec;185:100-108. Epub 2016 Aug 26 PubMed.

    View all comments by Oleg Butovsky

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  1. DAMned to Death? Microglia May Proliferate to Senescence