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. 2023 May 22;12(10):3589.
doi: 10.3390/jcm12103589.

Association between Cerebrospinal Fluid Soluble TREM2, Alzheimer's Disease and Other Neurodegenerative Diseases

Wenchuan Zhou  1 , Yutong Zhou  1 , Jing Li  1
Affiliations

Association between Cerebrospinal Fluid Soluble TREM2, Alzheimer's Disease and Other Neurodegenerative Diseases

Wenchuan Zhou et al. J Clin Med. .

Abstract

Background: Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential biomarker and therapy target for neurodegenerative diseases (NDDs). The purpose of this meta-analysis was to investigate the association between CSF sTREM2 level and NDDs, and to reveal the dynamic changes in CSF sTREM2 level in Alzheimer's disease (AD) continuum.

Methods: We systematically searched PubMed, Embase, Web of Science, and Cochrane Library databases for observational studies, which compared the levels of CSF sTREM2 between NDDs and controls. Sources of heterogeneity were analyzed using sensitivity analysis, subgroup analysis and meta-regression. We assessed pooled data using a random-effects model.

Results: Twenty-two observational studies which included 5716 participates were identified. Compared with the controls, the whole AD continuum group showed a significant increase in CSF sTREM2 level (standardized mean difference [SMD]: 0.41, 95% confidence intervals [CI]: 0.24, 0.58, p < 0.001). The mild cognitive impairment (MCI) group displayed the largest effect size (SMD, 0.49 [95% CI: 0.10, 0.88], p = 0.014), followed by the AD cohort (SMD, 0.40 [95% CI: 0.18, 0.63], p < 0.001). The increase in sTREM2 in the preclinical stage of AD (pre-AD) group was the lowest (SMD, 0.29 [95% CI: 0.03, 0.55], p = 0.031). Other NDDs also showed an increase in the CSF sTREM2 levels compared with control groups (SMD, 0.77 [95% CI: 0.37, 1.16], p < 0.001).

Conclusions: The pooled data confirmed that NDDs are associated with increased CSF sTREM2 level, thereby suggesting the CSF sTREM2 as a potential dynamic biomarker and therapy target for NDDs.

Keywords: Alzheimer’s disease; meta-analysis; neurodegenerative diseases; soluble TREM2.

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Conflict of interest statement

There is no conflict of interest related to the submitted paper.

Figures

Figure 1
Figure 1
Schematic diagrams of soluble TREM2 (sTREM2) generation and function. Canonical transcript (ENST00000373113) consists of five exons; immunoglobulin-like (Ig-like) domain and transmembrane (TM) domain are present in exon 2 and exon 4, respectively. The locations of some variants (p.Q33X, p.R47H, p.R62H, p.T66M, p.D87N, p.H157Y and p.L211P) are shown in the canonical TREM2 domain. ADAM10/ADAM17 sheddase cleave TREM2 receptor on histidine 157, contributing to the liberation of sTREM2. The C-terminal fragment is further cut by γ-secretase from the membrane. ENST00000373122 transcript lacks exon 5, and ENST00000338469 transcript lacks exon 4. TREM2Δe2 transcript lacks exon 2 and retains all other exons. Upon TREM2–ligand interaction, two tyrosine residues in ITAM of DAP12 are phosphorylated followed by recruiting SYK that initiates activation of a cascade of signaling events, such as cell survival and proliferation, cell metabolism, actin cytoskeleton remodeling, and phagocytosis of apoptotic neurons. sTREM2 affects ligand binding capacity, prevents ligand binding to TREM2, and binds unknown receptors on other cells, thereby inhibiting TREM2 signaling.
Figure 2
Figure 2
Flow diagram for identifying eligible studies.
Figure 3
Figure 3
Comparison of CSF sTREM2 between the whole AD continuum (pre-AD, MCI and AD dementia) and control groups.
Figure 4
Figure 4
Comparison of CSF sTREM2 between other NDDs and control groups.
Figure 5
Figure 5
Subgroup analysis of CSF sTREM2 in AD dementia cohort based on measurement methods (ELISA and non-ELISA) of sTREM2.
See this image and copyright information in PMC

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