**4. TREM2 and AD**

TREM2 gives protection against neurodegenerative disease. Depletion of TREM2 can induce impaired phagocytosis of the critical substrates such as APOE [83] and exacerbates tau pathology in AD [84].

### **4.1 TREM2 gets involved in AD pathogenesis via microglia**

TREM2 is found to reduce tau seeding in neuritic plaques [85], which is essential for synapse clearance in the early stage of brain development, and TREM2-KO mice demonstrate altered sociability [69]. Moreover, TREM2 can induce microglia to gather around Aβ and restrict plaque expansion found in murine models of AD [86].

### *Microglia, TREM2, and Therapeutic Methods of Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.100203*

Similar conditions can also lead to exacerbation of axonal dystrophy and dendritic spine loss [87]. Another research shows that a dosage of TREM2 can reprogram the microglial response in downregulating the expression of DAM genes and ameliorating the pathological phenotype in AD mice [88]. In the absence of functional TREM2, amyloid plaque seeding increased, and microglial aggregation decreased [88]. A similar study shows that in human pluripotent stem cell (PSC), monocytes and transdifferentiated microglia-like cells, TREM2 R47H variant and loss of TREM2 on heterozygous or homozygous, display a significant decreased in phagocytosis [89]. On a recent finding, IL-4 and IL-10 enhance the phagocytosis of microglia *via* upregulation of TREM2 [90]. These findings support the hypothesis that reactive microglia and TREM2 are functionally necessary to alleviate neuronal damage. However, other studies give opposite outcomes that loss of TREM2 may be protective in AD mice [91].

Genetically, the immune cell-specific phospholipase C isoform γ2 (PLCG2), a rare coding variant, is identified [92]. Recent research has demonstrated that TREM2 can mediate phagocytosis, cell survival, lipid metabolism, and process neuronal debris through PLCG2 of microglia derived from human-induced pluripotent stem cell (iPSC) [93]. PLCG2 P552R variant has protective functions including weak-enhancing enzyme functions [94] and promoting survival functions of microglia in Plcγ2-P522R knock in mice [95]. These studies highlighted the critical role of the TREM2 pathway in AD and provided genetic evidence for the increase of TREM2 in the pathologic process of AD.

In recent years, different TREM2 ligands have been found and proposed, such as β-amyloid peptide [96] and APOE [97]. APOE-dependent molecular signature in microglia is identified in AD patients, mediating a switch from homeostatic to neurodegenerative status [98]. This can be a target in treating AD patients through restoring the homeostatic microglia.
