. Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2021 Jan 19;118(3) PubMed.

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  1. In the current study the Colonna lab describes very similar properties of a new TREM2 agonistic antibody as in their previous paper using the Alector antibody AL002c which binds to the stalk region of TREM2 (Wang et al., 2020). 

    To us, it looks like hT2AB may also bind to the stalk region, N-terminal to the cleavage site, but we are not sure that the antibody is a true ligand surrogate. However, the antibody induces cross-linking, blocks shedding, and increases survival and signaling, findings very similar to those of our 4D9 antibody (Schlepckow et al., 2020) and other agonistic TREM2 antibodies published previously (summarized by Lewcock et al., 2020). 

    The current study, however, indicates that treatment with agonistic TREM2 antibodies may be saturable, since in vivo hT2AB failed to further activate microglia expressing the common variant of TREM2, while microglia expressing the hypomorphic R47H mutant were substantially activated. This may be expected, since the DAM signature evoked by TREM2 signaling is already extremely highly elevated in 5xFAD mice expressing wild-type (wt) TREM2. However, the in vivo data are somewhat inconsistent with the findings in bone marrow macrophages (BMMs), where the authors found stimulation of survival and reporter activity in cells expressing the common variant.

    Nevertheless, we don’t think one can use these findings as an argument that agonistic antibodies only rescue hypomorphic TREM2 functions, which would mean that such antibodies could only be used in the rare AD patients with TREM2 variants such as the R47H mutation. Based on our findings this is not the case. We observed protective effects of the 4D9 TREM2 antibody in cultured cells and in a mouse model for amyloidosis in the presence of wt TREM2 (Schlepckow et al., 2020). Similarly, it was reported that the Alector antibody AL002a also reduces amyloid pathology and behavioral abnormalities in the 5xFAD mice expressing wt TREM2 (Price et al., 2020).

    Moreover, in the ADNI cohort, we observed that higher levels of CSF TREM2 in AD patients without TREM2 variants associate with a better clinical outcome (Ewers et al., 2019), a finding which we confirmed now by investigating the longitudinal CSF samples of the DIAN cohort. Furthermore, more recently, antibody 4D9 was shown to promote beneficial microglial activity after demyelination injury in mice expressing endogenous wt TREM2 (Simons lab together with our lab; Bosch-Queralt et al., Nature Metabolism; in press). In addition, the Alector antibody AL002c also promotes remyelination in the presence of wt TREM2 in a mouse model for multiple sclerosis (Cignarella et al., 2020). 

    During AD microglia may fail to mount an appropriate response to the pathology, and such a reduced response could still be restored by agonistic TREM2 antibodies even in the absence of a TREM2 mutation. In that regard it is also important to note that all published agonistic TREM2 antibodies, including 4D9, and AL002 previously published by the Colonna lab (Wang et al., 2020), stimulate microglial survival and proliferation also in the presence of wt TREM2 (summarized by Lewcock et al., 2020).  Therefore, it appears that agonistic TREM2 antibodies can increase protective functions even if wt TREM2 is expressed. 

    Finally, it is worth noting that treatment with a microglia-modulating antibody may have to occur very early in the disease process, even before amyloid deposition, when microglia are not yet fully stimulated. This became evident by our finding that TREM2 is required to support microglia-mediated removal of amyloid seeds (Parhizkar et al., 2019). For a comparative detailed description of TREM2-modulating antibodies we refer to our recent review article (Lewcock et al., 2020). 

    References:

    . TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis. Acta Neuropathol. 2020 Oct;140(4):513-534. Epub 2020 Aug 9 PubMed.

    . Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease. Sci Transl Med. 2019 Aug 28;11(507) PubMed.

    . Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer's Disease. Neuron. 2020 Dec 9;108(5):801-821. Epub 2020 Oct 22 PubMed.

    . Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019 Feb;22(2):191-204. Epub 2019 Jan 7 PubMed.

    . 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.

    . 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.

    . Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med. 2020 Sep 7;217(9) PubMed.

  2. We thank Drs. Haass and Schlepckow for their comment. We agree that TREM2 agonist antibodies have been developed by other groups, an excellent body of work that we referenced and discussed in our paper.

    We would like to emphasize several points: First, Haass and Schlepckow compare our hT2AB findings with the results of their own studies with antibody clone 4D9 (Schlepckow et al., 2020) and with a study performed with the Alector antibody Al002a (Wang et al., 2020). We believe such a comparison is confounded by the fact that details on the exact binding epitope and mechanism by which the various antibodies activate TREM2 are lacking. It is well possible that the in vitro and in vivo effects of TREM2 engagement by these antibodies differ.

    Second, the major focus of our work was not on further defining the biophysical properties and mechanism of action of hT2AB, but on delineating how this antibody impacts microglia phenotypes in a mouse model of AD. This was achieved by unbiasedly identifying microglial cell type compositions and activation trajectories using high-throughput single-cell RNA sequencing. Using this approach, we reported that microglial cell type proportions differ in dependence of genotype, treatment, and sex covariates. By considering the observed baseline levels of microglia expansion in 5xFAD mice with various TREM2 genotypes, we concluded that the relative effect of the antibody was more evident in mice that carried the TREM2 R47H variant compared to mice carrying the common TREM2 variant. This is in agreement with previous work using the Al002a antibody.

    Importantly, we do not at all argue that agonistic antibodies can solely rescue hypomorphic TREM2 functions and consequently can only be used in the rare Alzheimer’s disease patients with TREM2 variants such as the R47H substitution. In fact, similarly to previous work with 4D9 and Al002a, we found that hT2AB stimulated proliferation of microglia with the common variant, but we also noted that this is dependent on the disease progression stage. However, we did not observe an hT2AB-mediated activation of microglia toward a DAM phenotype, corroborating earlier findings using the Al002a antibody.

    Overall, we would like to caution against extrapolating data obtained in the mouse models using surrogate antibodies to predict potential clinical implications. In this context, recent work from one of our labs demonstrated that gene transcription profiles in microglia from Alzheimer’s disease patients differ from those in the 5xFAD mouse model (Zhou et al., 2020). Finally, our observation that hT2AB-mediated effects on microglia are greatest where hTREM2 engagement is deficient or suboptimal is aligned with Haass and Schlepckow’s notion that treatment should start early in the disease process, at a stage were microglia are not yet fully stimulated. We strongly believe that our new findings contribute to a better understanding of how basal microglia activation state affects the impact of an agonistic TREM2 antibody on microglia.

    References:

    . 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.

    . Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med. 2020 Sep 7;217(9) PubMed.

    . Author Correction: Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. Nat Med. 2020 Jun;26(6):981. PubMed.

  3. This manuscript adds to the growing body of work supporting antibody-mediated agonism of TREM2 as a therapeutic approach for treatment of Alzheimer’s disease. These results are consistent with other studies demonstrating the impact of distinct TREM2 targeting antibodies (Fassler et al., 2021; Schlepckow et al., 2020) and previous results from the Colonna lab using a different TREM2 antibody generated at Alector (Wang et al., 2020).

    Although there are notable differences between studies, taken together these results provide important cross-validation that activation of the TREM2 pathway shifts microglia toward a disease-modifying state, and further supports the therapeutic hypothesis set forth by the understanding of the molecular genetics of human TREM2 variants that increase AD risk. Our hope is that the consistency of results with TREM2 agonist antibodies points toward promising potential for translatability to clinical studies.

    The authors suggest that an important implication of this work is that it suggests the level of TREM2 signaling in microglia is saturable. Based on the data in this manuscript and their previous work, this is a logical inference, as stronger transcriptional effects have been observed with TREM2 antibody treatment in R47H mice. They also note that the stage of disease can impact outcome, because microglia in these models may have maximal TREM2 signaling prior to treatment.

    However, as these studies were conducted at one dose level in a single mouse model, other possibilities exist that may explain this data. For instance, higher or long-term dosing of this antibody could provide benefits in both wild-type and R47H carriers and bears further investigation. Replication of these findings and investigation of additional endpoints across different AD mouse models and antibodies is required to determine the key variables that impact the efficacy of this therapeutic approach.

    Another key question that will benefit from additional study is to what extent transcriptional responses translate to functional cellular effects and whether a sufficient state is achieved to impact disease-relevant endpoints in both CV and R47H models. Efficacy studies measuring additional endpoints will be required to address these questions and their impact on neurons and other CNS cell types upon chronic dosing. Multiple groups, including our own, have observed therapeutic effects in amyloid-plaque-bearing mice expressing wild-type TREM2, indicating benefits can be observed in the absence of TREM2 mutations.

    Importantly, it must also be determined which of the microglial states found in AD mouse models (if any) most accurately represents the human brain. For this reason, further deep sequencing of microglial states in human AD and biomarker studies measuring the extent and effects of TREM2 activation will be critical in defining both the target patient population and efficacious dose.

    References:

    . Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer's disease models. J Neuroinflammation. 2021 Jan 9;18(1):19. PubMed.

    . 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.

    . 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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