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Kawabori M, Kacimi R, Kauppinen T, Calosing C, Kim JY, Hsieh CL, Nakamura MC, Yenari MA. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J Neurosci. 2015 Feb 25;35(8):3384-96. PubMed.
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Icahn School of Medicine at Mount Sinai
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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