Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, Ward M, Siddiqui O, Paul R, Gilfillan S, Ibrahim A, Rhinn H, Tassi I, Rosenthal A, Schwabe T, Colonna M. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med. 2020 Sep 7;217(9) PubMed.

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  1. We read this article with great interest. This work provides a convincing confirmation of the value of TREM2 agonist antibodies in mouse models of AD while providing new details on the impact of these antibodies on microglial state through single-cell RNA-Seq.

    There are significant efforts underway in industry and academia to target TREM2 through the development of antibodies designed to enhance TREM2 function (Deczkowska et al., 2020) based on the strong genetic evidence demonstrating that TREM2 loss-of-function increases disease risk and promotes disease progression. Wang et al. describe a new therapeutic antibody named AL002c, adding to the growing list of these tools. Early work by Takahashi et al. (2005) showed that cross-linking an N-terminally tagged version of TREM2 stimulates the ERK pathway and promotes chemotaxis and phagocytosis.

    Studies with antibodies by Amgen (Cheng et al., 2018), and now by Alector, along with our previously published 4D9 antibody (Schlepckow et al., 2020), promote numerous protective microglial functions. Surprisingly, both 4D9 and AL002c recognize epitopes in the stalk region close to and around the ADAM10/17 cleavage site after amino acid 157 in TREM2 (Schlepckow et al., 2017). Thus, both antibodies appear to share similar mechanisms of action, namely inhibition of TREM2 shedding and direct receptor agonism. Both 4D9 and AL002c promote TREM2 signaling, thus stimulating microglia survival and proliferation as well as phagocytosis.

    Wang et al. demonstrate that AL002c also promotes a molecular signature suggesting metabolic activation and proliferation in the 5XFAD model on an hTREM2 R47H transgenic background. This is consistent with reversal of loss-of-function phenotypes that result in survival defects and deficient cellular and brain metabolism (Ulland et al., 2017; Kleinberger et al., 2017). The single-cell RNA-Seq in this study provides a large dataset demonstrating an impact of TREM2 agonist antibodies on microglial cell state that correlates with a beneficial effect on other disease-relevant endpoints. Our recent work shows that 4D9 treatment results in a similar effect, as observed through a reduction in expression of the homeostatic marker P2RY12 and increased TREM2 expression suggesting a DAM-like microglia state transition.

    Wang et al. also demonstrate that AL002c reduced neuritic dystrophies and filamentous plaques without affecting compact plaques in 5xFAD mice. This is in contrast to our recent study, which demonstrated that treatment with 4D9 led to a reduction in plaque load. However, this discrepancy can be explained based on previous characterization of these mouse models showing that plaques are less dense in APP KI compared to 5XFAD mice. This, along with additional characterization of plaque composition, suggests that the reduction of plaque load observed in our study represents the removal of the plaque halo as the dense plaque cores were not affected, as in Wang et al.

    The reduction in soluble TREM2 in the cerebrospinal fluid by AL002c could potentially be used as a biomarker of target engagement, although it is not clear if this reduction is due to reduced shedding, enhanced uptake of antibody-bound TREM2, or a combination of these mechanisms. Further understanding of alterations of soluble TREM2 levels in CSF will be needed to properly interpret this readout as a target engagement biomarker.

    This is a very exciting advancement, as AL002c appears well-tolerated in a human Phase 1 study, though there are many outstanding questions to tackle to best deploy novel treatments for Alzheimer’s disease, including:

    • What patient population would benefit most from a TREM2 therapy?
    • When during disease progression is best to intervene?
    • What is the durability of microglia activation, and can protective functions be maintained during chronic disease treatment?
    • What is the role of soluble TREM2?
    • What is the impact of microglia therapies on synaptic pruning and neuronal health during chronic dosing?

    References:

    Deczkowska A, Weiner A, Amit I. The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway. Cell. 2020 Jun 11;181(6):1207-1217. PubMed.

    Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med. 2005 Feb 21;201(4):647-57. PubMed.

    Cheng Q, Danao J, Talreja S, Wen P, Yin J, Sun N, Li CM, Chui D, Tran D, Koirala S, Chen H, Foltz IN, Wang S, Sambashivan S. TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer's disease variant Trem2 R47H on murine myeloid cell function. J Biol Chem. 2018 Aug 10;293(32):12620-12633. Epub 2018 Mar 29 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.

    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.

    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.

    Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, Focke C, Deußing M, Suárez-Calvet M, Mazaheri F, Parhizkar S, Pettkus N, Wurst W, Feederle R, Bartenstein P, Mueggler T, Arzberger T, Knuesel I, Rominger A, Haass C. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017 Jul 3;36(13):1837-1853. Epub 2017 May 30 PubMed.

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