TREM2 and sTREM2 in Alzheimer's disease: from mechanisms to therapies

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor predominantly expressed by microglia in the brain. Recent studies have established TREM2 as a central immune signaling hub in neurodegeneration, where it triggers immune responses upon sensing pathological development and tissue damages. TREM2 binds diverse ligands and activates downstream pathways that regulate microglial phagocytosis, inflammatory responses, and metabolic reprogramming. Interestingly, TREM2 exists both in its membrane-bound form and as a soluble variant (sTREM2), that latter is generated through proteolytic shedding or alternative splicing and can be detected in cerebrospinal fluid and plasma. Emerging clinical and preclinical evidence underscores the potential of TREM2 and sTREM2 as diagnostic biomarkers and therapeutic targets in Alzheimer's disease (AD). This review provides a comprehensive overview of the molecular functions, regulatory mechanisms, and pathological implications of TREM2 and sTREM2 in AD. Furthermore, we explore their potential roles in diagnostics and therapeutics while suggesting key research directions for advancing TREM2/sTREM2-based strategies in combating AD.

Keywords: Alzheimer’s disease; Amyloid; Metabolism; Microglia; Neurodegeneration; TREM2; Tau; sTREM2.

Fig. 1

Schematic illustration of TREM2 signaling. The membrane-bound TREM2 receptor interacts with various ligands, including lipids, lipoproteins, apolipoproteins and amyloid-β. Ligand binding to TREM2 triggers the phosphorylation of tyrosine residues within the ITAM motif of the DAP12 cytoplasmic domain by SRC family kinases. The phosphorylated ITAM recruit the protein tyrosine kinase SYK to activate downstream signaling pathways. Additionally, TREM2 can associate with DAP10 homodimer, which contains YXNM motifs. These motifs directly recruit PI3K, activating further signaling pathways. SYK activation drives key pathways, including PLCγ2, Rac1/Cdc42, ERK, and PI3K. PLCγ2 activation is critical for microglial phagocytosis and lipid metabolism. Meanwhile, Rac1/Cdc42-GTPase signaling plays a key role in cytoskeletal remodeling and cell migration. Additionally, the ERK pathway is essential for microglial survival, proliferation, and inflammatory responses. In parallel, the PI3K/Akt pathway, activated by both DAP10 and SYK, governs essential cellular processes such as survival, proliferation, and glucose metabolism. PIP3, phosphatidylinositol 3,4,5-trisphosphate; PIP2, phosphatidylinositol (4,5)-bisphosphate; PLCγ2, phospholipase Cγ2; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PKC, protein kinase C; PI3K, phosphatidylinositol 3-kinase; ERK, extracellular signal-regulated kinase; GSK3β, glycogen synthase kinase 3β; mTOR, mechanistic target of rapamycin

Fig. 2

Roles of TREM2 in Alzheimer’s disease pathology. In the presence of TREM2, amyloid plaque accumulation activates the disease-associated microglia (DAM) program and/or the microglial neurodegenerative (MGnD) phenotype. Microglia cluster around plaques, trimming the peripheral region of amyloid-β fibrils and compacting the plaque structure. Additionally, they form a protective barrier between plaques and surrounding neural tissue, reducing amyloid-β-induced neuritic dystrophy. In contrast, TREM2 deficiency or mutation disrupts the activation of DAM and/or the MGnD phenotype, significantly decreasing the number of plaque-associated microglia. This results in the formation of loosely packed amyloid-β plaques termed filamentous plaque, accompanied by more severe neuritic dystrophy in adjacent areas. Consequently, tau pathology becomes more pronounced, promoting its accumulation and propagation, which ultimately accelerates neuronal loss

Fig. 3

Schematic illustration of sTREM2 production in microglia. This diagram illustrates two primary mechanisms underlying the generation of sTREM2: the proteolytic cleavage pathway and the splicing pathway. In the proteolytic cleavage pathway, the ectodomain of TREM2 is cleaved by metalloproteases, with ADAM10/17 cleaving at the H157-S158 bond and meprin β cleaving at the R136-D137 bond, resulting in the release of sTREM2 into the extracellular space. Alternatively, in the splicing pathway, mRNA variants of TREM2 are generated through splicing events, producing soluble forms of TREM2 that are also released extracellularly. Specifically, ENST00000373113 represents the canonical TREM2 transcript, consisting of five exons, while ENST00000338469 lacks exon 4, which encodes the transmembrane domain. Additionally, ENST00000373122 lacks exon 5 and has an alternative start site at exon 4, resulting in a different coding sequence. The box in the middle highlights the genetic modifiers influencing sTREM2 levels in the CSF

Fig. 4

Dynamic changes of sTREM2 across AD spectrum. (A) The levels of sTREM2 in CSF gradually increase throughout the AD continuum, correlating with microglial activation. This increase reaches its peak during the mild cognitive impairment (MCI) stage and subsequently plateaus or even declines in the dementia stage. (B) In elderly individuals, higher baseline CSF sTREM2 concentrations are associated with slower cognitive decline, particularly in memory and overall cognition. Furthermore, elevated sTREM2 levels correlate with a slower rate of hippocampal atrophy

Fig. 5

Potential roles of sTREM2 in Alzheimer’s disease pathology. The sTREM2, generated upon microglial activation, plays a crucial role in modulating AD pathology. It has been shown to inhibit Aβ oligomerization, fibrillization, and neurotoxicity. Additionally, sTREM2 promotes microglial activation, enhancing several microglial functions, including increased cell proliferation, migration, clustering around amyloid plaques, and the uptake and degradation of Aβ. These actions collectively reduce amyloid plaque burden and the number of dystrophic neurites. Additionally, sTREM2 interacts with transgelin-2 (TG2), leading to the deactivation of GSK3β and reducing tau phosphorylation. This process helps prevent neuronal loss and alleviates cognitive and behavioral impairments