. 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.


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  1. Neuroinflammatory mechanisms have emerged as an important feature and pathogenic event in Alzheimer’s disease. Recently, mutations in TREM2 have been identified as risk factors for the development of the sporadic type of this neurodegenerative disease. In this study, the Colonna group publishes the first profound analysis of microglial TREM2 function in murine AD models. One of the most intriguing findings of this study is that TREM2-deficient microglia seem to show an impaired reaction to Aβ deposition. Since TREM2-deficient 5xFAD mice showed an increase in the overall Aβ load in the hippocampus, this suggest that, at the investigated time point, TREM2 mediated mechanisms that restrict the deposition of Aβ. In keeping with this, TREM2 deficiency impaired microglial recruitment to the site of Aβ deposition. Importantly, the authors excluded, at least by in vitro experiments, that TREM2 deficiency affects microglia Aβ phagocytosis or degradation directly.

    Instead TREM2 seems to be involved in microglial survival mechanisms and TREM2 deficiency increased microglial apoptosis, possibly linked to restricted colony-stimulating factor 1 levels. Alternatively, TREM2-deficient cells may harm themselves by an increased release of TNFα, although several types of microglial cell death need to be considered (Kim and Li , 2013; Jung et al.  2005). Thus, TREM2-deficient microglia seem to not  survive the Aβ challenge and therefore fail to mount an appropriate clearance response, in line with previous findings showing that improving microglial phagocytosis in vivo can restrict Aβ deposition (Heneka et al., 2013).

    Another important finding of this study is that TREM2 is not activated by Aβ itself, as previously suggested, but by certain anionic membrane phospholipids, a a response that  was severely limited by the human R47H mutation, which has been linked to sporadic AD. Therefore, TREM2 expression at Aβ plaque sites (Frank et al., 2008Lue et al., 2014) can be interpreted as an attempt to survive the local inflammatory and toxic milieu, a prerequisite to restrict Aβ accumulation by phagocytosis or release of degrading proteases.

    Overall this study further highlights the role of microglia in neurodegeneration and in particular in Alzheimer’s disease. Similar to previous studies, (e.g., Bradshaw et al., 2013) it points to microglial uptake and degradation of Aβ as an important method for restricting the peptide's accumulation. Given the plethora of GWAS-identified mutations that are potentially linked to immune function (Lambert et al.,  2013), it can be expected that further disease-relevant microglial functions will be discovered.

    Naturally, these findings fuel the hope of developing therapeutics that modify microglia functions. For this to be successful, we need to consider not only the different innate immune mechanisms, but the precise disease stage when they manifest.


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  2. The results of these two papers are consistent with a model of AD etiology that can be derived from the network analysis of AD (Rosenthal and Kamboh, 2014; Zhang et al., 2013) and TREM2 (Forabosco et al., 2013). This model strongly implicates dysregulation of efferocytosis (i.e., apoptotic cell clearance or, more generally, defective clearance of cellular "debris") in the etiology of AD.

    For example, the three major "pathways" previously shown to be enriched in GWA studies for LOAD (lipid/sterol efflux, innate immune cell function, and endocytosis) (Jones et al., 2010) are key components of efferocytosis (Ravichandran and Lorenz, 2007; Poon et al., 2014; A-González and Castrillo, 2010). Moreover, network analysis of human genetic variants associated with LOAD (Rosenthal and Kamboh, 2014) or of human brain gene co-expression data associated with TREM2 (Forabosco et al., 2013) also points to efferocytosis. This scavenging function of microglia and macrophages is critical to inflammation resolution and tissue repair after infection and injury. However, it is also known to play an important role in the maintenance of tissue homeostasis (Davies et al., 2013).

    A better understanding of 1) the role of efferocytosis/clearance of cellular “debris” in the maintenance of brain tissue (including myelin and synapses) and 2) the gene network that supports this biological process (which is likely to include APOE, TREM2, TREML2, ABCA7 [an orthologue of the C. elegans efferocytosis gene ced-7], ABCA1, MEGF10, ABCG1, ELMO1, SORL1/retromer, C1Q, LXR, RXR, TRIP4, and several other candidate AD loci/genes) (Hsieh et al., 2009; Takahashi et al., 2005; de Freitas et al., 2012; Jehle et al., 2006; Hamon et al., 2006; Yvan-Charvet et al., 2010; Cash et al., 2012; Kiss et al., 2006; A-Gonzalez et al., 2009; Ruiz et al., 2014) could shed some light on the mystery of AD etiology beyond the amyloid hypothesis (Seong and Matzinger, 2004; Medzhitov 2008; Kotas and Medzhitov, 2015) and inspire the development of novel therapeutic approaches for this devastating disease (Schadt et al., 2009).  


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    View all comments by Edoardo Marcora
  3. The intriguing finding of the Wang et al. study is that lipids “activate” wild-type TREM2 and turn on NFAT signaling pathways whereas the R47H variant of TREM2, which is a risk allele for AD, PD, FTD, and ALS, is almost completely inactive in the NFAT reporter assay.

    NFAT singling regulates expression of pro-inflammatory cytokines TNF-α, IL-2, IFNg, etc. Thus, the charged lipids—presumably released from apoptotic neurons and coating the amyloid plaques—should activate WT microglia and stimulate the release of inflammatory cytokines, whereas those expressing R47H-TREM2 should not. By implication, WT-TREM2 should be proinflammatory and R47H-TREM2 should not promote inflammation in response to apoptotic cells. This seems to run counterintuitive to the common finding that increased inflammation is observed in the brains of patients with all four neurodegenerative diseases indicated above, and there is increasing evidence that chronic neuroinflammation is toxic to the brain function and initiates neurodegeneration.

    One thing to keep in mind is that the NFAT reporter assay was performed by overexpressing WT-TREM2 or R47H-TREM2 in 2B4 reporter T-cells. TREM2 has an extremely short cytoplasmic tail and is known to signal by binding another membrane protein ,DAP12/TYRO-BP, which possesses a longer cytoplasmic tail with an immunoreceptor tyrosine-based activation (ITAM) motif. From the information in the manuscript, it seems that Wang et al. transfected TREM2 alone and not TREM2+DAP12. Also unclear is whether 2B4 T-cells express endogenous DAP12 and if so, what the stoichiometry of overexpressed TREM2 to endogenous DAP12 is. Thus, at present it remains an open question whether the effects of R47H mutation on NFAT signaling reported here shed any light on the role of TREM2 in AD pathogenesis or are due to overexpression of the protein in a non-microglial cell line. Future studies will need to resolve the conundrum of how R47H-TREM2, which does not seem to promote inflammation, increases the risk for neurodegeneration.

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