Roles of TREM2 in the Pathological Mechanism and the Therapeutic Strategies of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is an age-related degenerative disease, which is characteristic by the deposition of senile plaques (SP) outside the cells, the neurofibrillary tangles (NFTs) inside the neurons, and the loss of synapse and neurons. Neuroinflammation may play an important role in the pathogenesis of AD. Microglia are the immune cells in the central nervous system. However, microglia might become disease-related microglia (DAMs) when stimulated by the external environment. DAMs have been shown to be involved in a series of events of AD development including Aβ accumulation and tau phosphorylation. The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor that is mainly expressed by microglia in the central nervous system (CNS). TREM2 plays an important role in the physiological function of microglia, and the dyshomeostasis of TREM2 is related to the development of late-onset AD. This article summarized the latest advances in TREM2 biology and its impact on the roles of microglia in AD development, with a particular emphasis on the structure, ligands, signal transduction, and the agonistic antibodies of TREM2 for AD treatment. We further discussed the survival, migration, phagocytosis, inflammation, and cellular metabolism of microglia, as well as the role of sTREM2 in neuroprotection and as a biomarker for AD. It provides a reference for further research on the molecular mechanism of microglial TREM2 in the occurrence and development of AD and on the therapeutic strategies targeted on the microglial TREM2.

Keywords: Alzheimer’s disease (AD); Aβ; microglia; monoclonal antibody; triggering receptor expressed on myeloid cells 2 (TREM2).

Figure 1

Structure of the human TREM2 gene and protein A: TREM2 gene, containing the exon (number box) and intron (line) sequences. B: TREM2 protein structure, including the signal peptide (SP) (1–18 aa), immunoglobulin Ig domain (19–134 aa), short stalk sequence (135–171 aa) in the extracellular region ETD (19–174 aa), and transmembrane (TM) region (175–195 aa) and intracellular region (196-230 aa). Arrows indicate the α-secretase and γ-secretase cleavage sites, respectively. The α-secretase cleaves TREM2 at the His157-Ser158 site. Two common AD-related variants, R47H and R62H, are present in the Ig domain, and the Ig domain may be involved in a key function mediated by TREM2 signaling.

Figure 2

TREM2 signaling pathway TREM2=myeloid cell trigger receptor 2; sTREM2=soluble TREM2; ApoE=apolipoprotein E; HDL=high-density lipoprotein; LPS=lipopolysaccharide; DAP12=DNAX activator protein 12; DAP10=DNAX-activated protein 10; ITAM=immune receptor tyrosine activation motif; SYK=splenic tyrosine kinase; PI3K=Phosphatidylinositol 3-kinase; AKT= serine / threonine protein kinase; MTOR=target of rapamycin; PIP3=3, 4,5-phosphatidylinositol triphosphate; P1P2=phosphatidylinositol-4, 5-bisphosphate; PLC-γ=PLC-γ; phospholipase; IP3=1, 4,5-inositol triphosphate; DAG=diglyceride; NF-κB=nuclear factor κB; MAPK=mitogen-activated protein kinase; hypoxia inducible factor-1α=HIF1α; Vav guanine nucleotide exchange factor 2/3=VAV2/3; GRB2=growth factor receptor-bound protein 2; SOS1=son of sevenless 1; RAS=rat sarcoma; ERK=extracellular signal-regulated kinase; Arp2=actin-related protein 2; Arp3=actin-related protein 3; β-catenin=beta-catenin; SRC= proto-oncogene c-Src protein tyrosine kinase; GSK3β=glycogen synthase kinase 3β; TG2=transglutaminase 2; ROCK=Rho-associated coiled-coil-containing protein kinase; ATP=Adenosine triphosphate; NADH=nicotinamide adenine dinucleotide Hydrogen; FADH₂=flavin adenine dinucleotide reduced; ADAM10/17=a disintegrin and metalloprotease domain-containing protein 10/17; DOK3=downstream of kinase 3.

Figure 3

Mechanism of TREM2 affecting microglial function in AD TREM2=myeloid cell trigger receptor 2; sTREM2=soluble TREM2; ApoE=Apolipoprotein E; LPS=lipopolysaccharide; DOK3=downstream of kinase 3; PI=phosphatidylinositol; DAP12= DNAX activation protein 12; DAP10=DNAX activation protein 10; SYK=spleen tyrosine kinase; PI3K=phosphatidylinositol 3-kinase; AKT=RAC-alpha serine/threonine-protein kinase; mTOR=mammalian targets of the rapamycin; mTORC 1=mammalian targets of the rapamycin complex 1; mTORC 2=mammalian targets of the rapamycin 2; NF-κB=nuclear factor κB; MAPK=mitogen activated protein kinase; TLR4=Toll like receptor 4; IL-1β= interleukin-1β; TNF-α=tumor necrosis factor-α; TGF-β1=transforming growth factor-β1; β-catenin=beta-catenin; ATP=adenosine triphosphate; NADH=nicotinamide adenine dinucleotide hydrogen; FADH₂=Flavin adenine dinucleotide reduced; CD33=cluster of differentiation 33; ADAM10/17=a disintegrin and metalloprotease domain-containing protein 10/17; IP3R=inositol 1,4,5-trisphosphate receptor; PLC-γ = phospholipase c-γ; IP =interferon inducible protein