Zhong L, Xu Y, Zhuo R, Wang T, Wang K, Huang R, Wang D, Gao Y, Zhu Y, Sheng X, Chen K, Wang N, Zhu L, Can D, Marten Y, Shinohara M, Liu CC, Du D, Sun H, Wen L, Xu H, Bu G, Chen XF. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model. Nat Commun. 2019 Mar 25;10(1):1365. PubMed.

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  1. I find it very interesting that sTREM2 can promote functions that we thought are associated with membrane bound full-length TREM2. This indeed makes therapeutic modulation of TREM2 even more tricky, since we now have not only to consider “overactivation” of microglia but maybe even reduced sTREM2 function. Combined with increased ApoE expression by microglia in disease-associated states, modulation of microglia activity is a huge challenge. Identification of the sTREM2 receptor on microglia may now shed more light on the more and more complicated life of these cells.

    View all comments by Christian Haass

  2. TREM2 is a type-I transmembrane protein that can undergo proteolytic shedding to release its Ig-like domain as a soluble protein, termed sTREM2, into the extracellular space. It can be readily detected in biological fluids, including the cerebrospinal fluid (CSF). Shedding is mediated by ADAM proteases and occurs at a defined amino acid position after histidine 157 (Schlepckow et al., 2017; Thornton et al., 2017). Additionally, alternative splice variants have been identified in human brain that code for sTREM2 with a slightly altered C-terminus (Jin et al., 2014). 

    So far we know that in mouse models of amyloidosis sTREM2 levels increase dramatically (Brendel et al., 2017), while in humans the increase is moderate with a peak around the time of symptom onset with significant increased TREM2 levels starting from five years before until approximately five years after expected years of symptom onset (Suarez-Calvet et al., 2016). So far the physiological and pathophysiological role of sTREM2 remains largely understudied.

    With the present study the authors follow up on a first study where they reported a positive effect of sTREM2 on microglial survival and a stimulatory effect on the production of inflammatory cytokines, which is not dependent on the presence of TREM2 or DAP12 (Zhong et al., 2017). Now the authors extend their investigation to the effects of administering sTREM2 (in different ways) and show a positive effect on microglia recruitment to the sites of amyloid plaques, leading to a reduction in overall plaque size and pointing to a protective role of wild-type sTREM2.

    It would have been interesting to see, in the manuscript, if mutant forms of sTREM2 (e.g., p.R47H) would have shown a similar loss-of-function phenotype as has been described for the full-length mutant receptor. So far the full-length receptor has been associated with beneficial functions (e.g., microglial recruitment to the amyloid plaque sites) and a proof-of-principle experiment indicated that stabilizing full-length TREM2 results in increased phagocytic activity (Kleinberger et al., 2014). Furthermore, increased production of sTREM2 due to the presence of the p.H157Y variant has been associated with increased risk for developing AD in a Han Chinese population (Jiang et al., 2016). Studies like this one by Zhong and colleagues are crucial to understand the functions of both full-length receptor and its cleaved ectodomain and are extremely instrumental in helping to design strategies to therapeutically target TREM2.

    References:

    Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med. 2017 Oct;9(10):1356-1365. PubMed.

    Thornton P, Sevalle J, Deery MJ, Fraser G, Zhou Y, Ståhl S, Franssen EH, Dodd RB, Qamar S, Gomez Perez-Nievas B, Nicol LS, Eketjäll S, Revell J, Jones C, Billinton A, St George-Hyslop PH, Chessell I, Crowther DC. TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant. EMBO Mol Med. 2017 Oct;9(10):1366-1378. PubMed.

    Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, Norton JB, Hsu S, Harari O, Cai Y, Bertelsen S, Goate AM, Cruchaga C. Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet. 2014 Nov 1;23(21):5838-46. Epub 2014 Jun 4 PubMed.

    Brendel M, Kleinberger G, Probst F, Jaworska A, Overhoff F, Blume T, Albert NL, Carlsen J, Lindner S, Gildehaus FJ, Ozmen L, Suárez-Calvet M, Bartenstein P, Baumann K, Ewers M, Herms J, Haass C, Rominger A. Increase of TREM2 during Aging of an Alzheimer's Disease Mouse Model Is Paralleled by Microglial Activation and Amyloidosis. Front Aging Neurosci. 2017;9:8. Epub 2017 Jan 31 PubMed.

    Suárez-Calvet M, Araque Caballero MÁ, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, Levin J, Danek A, Ewers M, Haass C, Dominantly Inherited Alzheimer Network. Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. Sci Transl Med. 2016 Dec 14;8(369):369ra178. PubMed.

    Zhong L, Chen XF, Wang T, Wang Z, Liao C, Wang Z, Huang R, Wang D, Li X, Wu L, Jia L, Zheng H, Painter M, Atagi Y, Liu CC, Zhang YW, Fryer JD, Xu H, Bu G. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med. 2017 Mar 6;214(3):597-607. Epub 2017 Feb 16 PubMed.

    Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N, Wenninger-Weinzierl A, Mazaheri F, Tahirovic S, Lleó A, Alcolea D, Fortea J, Willem M, Lammich S, Molinuevo JL, Sánchez-Valle R, Antonell A, Ramirez A, Heneka MT, Sleegers K, van der Zee J, Martin JJ, Engelborghs S, Demirtas-Tatlidede A, Zetterberg H, Van Broeckhoven C, Gurvit H, Wyss-Coray T, Hardy J, Colonna M, Haass C. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.

    Jiang T, Tan L, Chen Q, Tan MS, Zhou JS, Zhu XC, Lu H, Wang HF, Zhang YD, Yu JT. A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese. Neurobiol Aging. 2016 Jun;42:217.e1-3. Epub 2016 Mar 3 PubMed.

    View all comments by Gernot Kleinberger

  3. The paper is remarkable as it implies that even a single dose of sTREM2 protein can ameliorate AD pathology by microglia. It would be important to study the effects of repeated injection of sTREM2 at different phases of AD pathology to test the potential use of sTREM2 as a therapeutic agent. In addition, it would also be interesting to see which cell types in the CNS can be affected by administration of soluble TREM2, since sTREM2 possesses the tendency to contact any cell type in the brain, as reported by the authors. An exciting goal for future studies is the identification of the receptors of sTREM2 in the CNS.

    View all comments by Shoutang Wang

  4. Zhong and colleagues have recently reported a remarkable series of findings that demonstrate that soluble forms of TREM2 exhibit cell-autonomous actions and act to mitigate AD pathogenesis in mouse models of AD. These observations serve to focus attention on the biological roles of soluble TREM2 (sTREM2). There is compelling evidence demonstrating that CSF levels of sTREM2 correlate with AD progression, and there are genetic links between the abundance of these species and risk of AD. The discovery that soluble forms of the receptor are generated through proteolytic cleavage of its extracellular domain, and that sTREM2 is found at increased levels in the CSF in AD patients, provides a potential biomarker for AD pathogenesis. However, the biological significance of sTREM2 in CSF is not understood and is poorly explored. The possibility that sTREM2 has cell autonomous actions is provocative and potentially of substantial importance. The present study is of particular interest, but ultimately unsatisfying in that their findings are largely phenomenological and the paper does not engage many of the central issues raised by their studies.

    It has been speculated that the proteolytic cleavage of Trem2, liberating its extracellular domain into the interstitial fluid, represents the functional inactivation of the full-length, membrane-associated receptor, which is thought to be deleterious with respect to disease pathogenesis. Moreover, sTREM2 species, acting as a decoy, might logically suppress microglial TREM2 activation by binding its ligands. Indeed, therapeutics directed at inhibiting this cleavage are under development. However, the present paper makes the opposite argument, whereby sTREM2 elicits a broad range of salutary actions by microglia that mimic those associated with activation of the full-length, membrane-associated TREM2.

    This present study by Zhong and colleagues follows their previous report that sTREM2 species exhibit microglial-directed, cell-autonomous actions, stimulating pro-inflammatory gene expression and enhancing microglial survival and proliferation (Zhong et al., 2017). The authors now report a large number of findings which result in a hypothesis that is hard to fathom.

    They show that injection of a purified form of sTREM2 stimulates a variety of microglial phenotypic changes and a reduction in amyloid plaque load and dystrophic neurites. These effects are analogous to that observed with direct microglial TREM2 activation. They previously have shown that sTREM2 actions on microglia do not involve the membrane-bound, full-length receptor and elicited a very robust pro-inflammatory response. This latter response is, again, hard to reconcile with their hypothesis. It is unknown and unexplored how sTREM2 might interact with microglia in such an autocrine loop.

    It is difficult to deduce from the paper that the sTREM2 injected (6ug) comprised the entire extracellular domain (1-171) and resulted in supraphysiological concentrations of sTREM2. These experiments included only a vehicle control, and not an inactive protein control. It is only in a subset of subsequent studies that appropriate controls are performed with the biologically relevant sTREM2 (1-157) species and a heat-inactivated control. A different range of concerns arise from studies in which sTREM2 is overexpressed in the 5XFAD mice using an AAV construct that includes the entire extracellular domain, EGFP, and a tag that is expressed at levels about 500-fold over endogenous levels. In this setting sTREM2 protein is expressed largely from neurons, a cell type that does not express TREM2. I don’t think these experiments are interpretable.

    Colonna and colleagues reported sTREM2 was found to be associated with neurons and plaques, a finding reproduced in the present study (Song et al., 2018). These data suggest that there is robust expression of neuronal TREM2 ligands to which sTREM2 binds. It is curious that this observation was not vigorously investigated beyond determination that in vitro neuronal electrophysiological characteristics are unaffected by sTREM2. Zhong et al. find a remarkable effect of sTREM2 on LTP and argue that this is a microglial-mediated response, although it is not clear how this might be achieved.

    In summary, although this study reports very compelling datasets, the excitement surrounding these findings is undercut by the unusual experimental paradigms and confounding experimental design.

    Overall, the suggestion that sTREM2 has cell-autonomous actions is both provocative and important. Indeed, the broad range of potential actions reported by Zhong et al. puts the question of the biology of TREM2 in an entirely new perspective. However, the lack of a cogent and compelling hypothesis supported by the data undermines enthusiasm for this paper.

    References:

    Zhong L, Chen XF, Wang T, Wang Z, Liao C, Wang Z, Huang R, Wang D, Li X, Wu L, Jia L, Zheng H, Painter M, Atagi Y, Liu CC, Zhang YW, Fryer JD, Xu H, Bu G. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med. 2017 Mar 6;214(3):597-607. Epub 2017 Feb 16 PubMed.

    Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, Colonna M. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med. 2018 Mar 5;215(3):745-760. Epub 2018 Jan 10 PubMed.

    View all comments by Miguel Moutinho

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News

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