**3. Physiological function on microglia of TREM2**

Recent years have witnessed the central role of TREM2 as a hub in diverse pathology. TREM2 is a receptor that interacts with a variety of ligands, many of which are markers of tissue damage. TREM2 is a single-pass transmembrane protein known to regulate immune responses in peripheral macrophages through lipopolysaccharide binding and bacterial phagocytosis [55–57]. RNA-seq data were analyzed across human tissues to investigate TREM2 expression, and it has been confirmed that TREM2 is expressed physiologically in a small group of macrophages that are tissue specific [58]. In CNS, TREM2 is mostly expressed on microglia. In addition to the expression on microglia, the analysis also showed its expression in macrophages

from the adrenal gland, placenta, and adipose tissue [59]. TREM2 was thought to bind a wide range of molecules [60], and the interaction with different ligands can regulate the signal intensity and direction of TREM2 in turn [61]. Downstream signals mainly consist of those arrangements; for example, DAP10 is the key to activate extracellular signal regulated-kinase (ERK) and serine/threonine protein kinase (AKT1), while in murine macrophages, DAP12 is necessary for calcium mobilization [61–63]. Functional loss of TREM2 is related to polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) [64].

Mice lacking TREM2 had defects in survival and differentiation of myeloid cells [65], as well as osteopenia and loss of microglia in CNS [62, 66]. TREM2-lacking cells may undergo a similar differential process as normal cells do despite a reduced life cycle [67]. Microglia deprived of TREM2 or expressing T66M variant demonstrated the impaired process of brain glucose metabolism and cerebral perfusion [68]. Mice TREM2 was involved in synaptic pruning through a microglia-dependent way to shape neuronal circuitry [69]. In rodents, TREM2-positive macrophages are found to be important regulators related to hair follicle stem cells [70]. Additionally, in TREM2-deficient microglia, increased autophagic vesicles can be found with defective activation of mTOR pathways [63], which partially regulate autophagy [71].

Deletion or impairment of TREM2 was proved to be detrimental to phagocytosis of lipoproteins, cellular debris, bacteria, and Aβ [68, 72, 73]. Moreover, overexpression of TREM2 in cells that are not functionally phagocytic like Chinese hamster ovary (CHO) cells showed induced phagocytosis of apoptotic cells and bacteria [57, 72].

TREM2 was also found to ameliorate neuroinflammation and neuronal apoptosis *via* PI3K/AKT signaling pathway in 5xFAD mice [74, 75]. TREM2 overexpression can also rescue cognitive barriers by reducing neuroinflammation *via* JAK/STAT/ SOCS pathway [76] and the suppression of TREM2 demonstrated a defective ability to regulate the PI3K/Akt and NF-κB signaling pathways [77].

Recently, genome-wide association studies (GWAS) demonstrated a link between single-nucleotide polymorphisms (SNPs) and inflammation-related genes to increased AD risk, such as the R47H variant in TREM2 [78], which is one of the strongest genetic risk factors for AD [79]. TREM2 variant R47H, whose foundation was dysregulated peroxisome proliferator-activated receptor-γ (PPARγ)/p38MAPK signaling [80], was shown to decrease the expression of TREM2, thus deteriorating myeloid cell responses to Aβ pathology [81]. Furthermore, the R47H variants and R62H variants of TREM2 demonstrate a defective microglial transcriptional activation, implicating fully functional TREM2 seems to be the key for development of the human DAM [82].
