Paper
- Alzforum Recommends
Safaiyan S, Besson-Girard S, Kaya T, Cantuti-Castelvetri L, Liu L, Ji H, Schifferer M, Gouna G, Usifo F, Kannaiyan N, Fitzner D, Xiang X, Rossner MJ, Brendel M, Gokce O, Simons M. White matter aging drives microglial diversity. Neuron. 2021 Apr 7;109(7):1100-1117.e10. Epub 2021 Feb 18 PubMed.
Recommends
Please login to recommend the paper.
Comments
VIB-KU Leuven
VIB-UAntwerp
The efforts of several groups that have recently applied single-cell transcriptomics to characterize microglial populations in physiology and disease have converged to the description of microglial reactive phenotypes with overlapping signatures across development, aging, and various disease-related scenarios (Keren-Shaul et al., 2017; Friedman et al., 2018; Hammond et al., 2019; and others). In Alzheimer’s disease mouse models, homeostatic microglia undergo a progressive phenotypic transition toward a phagocytic-prone disease-associated state that was named DAM/MGnD/ARM, and that depends on TREM2/APOE signaling (Keren-Shaul et al., 2017; Krasemann et al., 2017; Sala Frigerio et al., 2019).
In this interesting work, Safaiyan et al. describe an aging-associated reactive microglial phenotype that is identified in the white matter of the aged mouse brain, referred to by the authors as white-matter-associated microglia (WAMs). WAMs share a gene-expression signature with DAMs, and like DAMs require TREM2 signaling for their phenotypic transition. The authors reanalyzed previously published scRNA-Seq datasets of mouse microglia in aging and disease (Sala Frigerio et al., 2019; Hammond et al., 2019), finding again the WAM signature. Surprisingly, WAMs do not depend on APOE in normal aging but cannot form in the absence of APOE in a mouse model of amyloidosis.
The finding of a DAM-like phenotype in white matter in aging and disease is important for understanding the full spectrum of microglial physiology. While accumulation of DAM-like cells was already shown in the aged mouse brain by our and other labs (Sala Frigerio et al., 2019; Hammond et al., 2019), this study shows their presence and specific peculiarities in white matter, where these cells operate their known surveillance activity by forming nodule structures to clear degenerated myelin.
Based on several lines of evidence, it is conceivable that WAMs are a specialized subtype of DAMs, e.g., their substantial overlap in signature, their increased phagocytic function, the dependency on TREM2 signalling, and the lack of unique WAM markers when compared to DAM. A similar transcriptomic signature the authors found in our dataset, which originated from dissected gray matter areas, also indicates strong similarity (Sala Frigerio et al., 2019). Additionally, the bioinformatic analysis of Safaiyan et al. suggests that WAMs may be an intermediate state in the trajectory toward full DAM activation, but further investigation is needed to characterize this conversion and how it may occur spatially. On the other hand, the authors also report that WAM forms normally in the absence of APOE in the aged brain, while ApoE is necessary in AD mice similarly to DAMs, suggesting these are two separate entities. This remains an interesting open question to be elucidated in the future.
Finally, lipid-droplet-accumulating microglia (LDAMs) recently have been described to accumulate with age in mouse and human brains (Marschallinger et al., 2020). This phagocytosis-deficient phenotype was described to be proinflammatory and to produce high levels of reactive oxygen species. It would be of interest to test whether LDAMs, which were reported to express a peculiar signature differing from DAMs, share part of their gene profile with WAMs or independently co-exist in the aging brain.
Recent large-scale, single-nuclei RNA-Seq showed human microglia to have a more complex heterogeneity than their murine counterparts (Gerrits et al., 2021), and we and others found strong species-specific differences with unique expression of genes related to neurodegeneration in human microglia (Geirsdottir et al., 2019; Mancuso et al., 2019). Thus, corroborating these findings in stem-cell derived microglia in vivo with xenotransplantation models would also be an important step forward in deciphering the complexity of human microglia biology (Mancuso et al., 2019; Fattorelli et al., 2021).
References:
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.
Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee SH, Haddick PC, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP, Hansen DV. Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models. Cell Rep. 2018 Jan 16;22(3):832-847. PubMed.
Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F, Segel M, Nemesh J, Marsh SE, Saunders A, Macosko E, Ginhoux F, Chen J, Franklin RJ, Piao X, McCarroll SA, Stevens B. Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity. 2019 Jan 15;50(1):253-271.e6. Epub 2018 Nov 21 PubMed.
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.
Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I, Schmidt I, Mancuso R, Chen WT, Woodbury ME, Srivastava G, Möller T, Hudry E, Das S, Saido T, Karran E, Hyman B, Perry VH, Fiers M, De Strooper B. The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques. Cell Rep. 2019 Apr 23;27(4):1293-1306.e6. PubMed.
Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, Pluvinage JV, Mathur V, Hahn O, Morgens DW, Kim J, Tevini J, Felder TK, Wolinski H, Bertozzi CR, Bassik MC, Aigner L, Wyss-Coray T. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020 Feb;23(2):194-208. Epub 2020 Jan 20 PubMed. Correction.
Gerrits E, Brouwer N, Kooistra SM, Woodbury ME, Vermeiren Y, Lambourne M, Mulder J, Kummer M, Möller T, Biber K, Dunnen WF, De Deyn PP, Eggen BJ, Boddeke EW. Distinct amyloid-β and tau-associated microglia profiles in Alzheimer's disease. Acta Neuropathol. 2021 May;141(5):681-696. Epub 2021 Feb 20 PubMed.
Geirsdottir L, David E, Keren-Shaul H, Weiner A, Bohlen SC, Neuber J, Balic A, Giladi A, Sheban F, Dutertre CA, Pfeifle C, Peri F, Raffo-Romero A, Vizioli J, Matiasek K, Scheiwe C, Meckel S, Mätz-Rensing K, van der Meer F, Thormodsson FR, Stadelmann C, Zilkha N, Kimchi T, Ginhoux F, Ulitsky I, Erny D, Amit I, Prinz M. Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program. Cell. 2019 Dec 12;179(7):1609-1622.e16. PubMed.
Mancuso R, Van Den Daele J, Fattorelli N, Wolfs L, Balusu S, Burton O, Liston A, Sierksma A, Fourne Y, Poovathingal S, Arranz-Mendiguren A, Sala Frigerio C, Claes C, Serneels L, Theys T, Perry VH, Verfaillie C, Fiers M, De Strooper B. Stem-cell-derived human microglia transplanted in mouse brain to study human disease. Nat Neurosci. 2019 Dec;22(12):2111-2116. Epub 2019 Oct 28 PubMed.
Fattorelli N, Martinez-Muriana A, Wolfs L, Geric I, De Strooper B, Mancuso R. Stem-cell-derived human microglia transplanted into mouse brain to study human disease. Nat Protoc. 2021 Feb;16(2):1013-1033. Epub 2021 Jan 11 PubMed.
View all comments by Nicola FattorelliBoston University School of Medicine
Safiyan, Besson-Girard, Gokce, Simons et al. identified white-matter-associated microglia named WAMs, which are an aging-specific microglial population. WAMs handle phagocytosis of demyelinating cellular debris, contributing to efferocytosis of apoptotic neurons (as shown with phosphatidylserine (PS)-receptor dependent engulfment) found in white matter of wild-type mice (Márquez-Ropero et al., 2020).
The team beautifully dissected subpopulations of microglia in transcriptomic and spatial manners and resolved a spectrum of microglia present in normal aging and diseases. In normal aging WT mice, 10 to 15 percent of microglia are WAMs, which share signatures and functions (lipid metabolism, phagocytosis, MHC class II gene activation) with previously identified disease-associated microglia (DAMs). WAMs are Trem2-dependent like DAMs, but ApoE-independent unlike DAMs. In aged AD mice, both WAMs and DAMs (20 percent and 40 percent, respectively, at 12 months) co-exist, depending on Trem2 and Apoe.
Interestingly, the authors showed that there are no differences in myelin binding and uptake between WT and Trem2 knockout microglia, likely because multiple PS receptors can engulf myelin debris. However, the degradation is reduced in Trem2 KOs due to reduced lysosomal proteins, e.g. Cathepsin L, indicating that Trem2 is critical for digestion of cellular debris.
From a therapeutic perspective, since WAMs appear before DAMs, targeting WAMs at an earlier Alzheimer’s disease stage could kill two birds with one stone, tackling effects of both aging and disease. Specifically improving Trem2 activity, on par with ongoing efforts in the field (Price et al., 2020; Schlepckow et al., 2020), or enhancing microglial digestion, are other strategies to enhance WAMs. Although the APOE dependency in AD and replications of the findings in humans have to be further explored, the authors’ finding of an aging-specific signature in microglia would impact broadly many age-associated diseases and open doors for targeted therapeutics.
References:
Márquez-Ropero M, Benito E, Plaza-Zabala A, Sierra A. Microglial Corpse Clearance: Lessons From Macrophages. Front Immunol. 2020;11:506. Epub 2020 Mar 27 PubMed.
Price BR, Sudduth TL, Weekman EM, Johnson S, Hawthorne D, Woolums A, Wilcock DM. Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition. J Neuroinflammation. 2020 Aug 14;17(1):238. PubMed.
Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, Willem M, Werner G, Pettkus N, Brunner B, Sülzen A, Nuscher B, Hampel H, Xiang X, Feederle R, Tahirovic S, Park JI, Prorok R, Mahon C, Liang CC, Shi J, Kim DJ, Sabelström H, Huang F, Di Paolo G, Simons M, Lewcock JW, Haass C. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med. 2020 Apr 7;12(4):e11227. Epub 2020 Mar 10 PubMed.
View all comments by Julia TCWMake a Comment
To make a comment you must login or register.