The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk

Abstract

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer’s Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10−15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

Functional insights from biophysical study of TREM2 interactions with ApoE and Aβ1-42

“…In addition, we show that TREM2 binds mAβ42 and inhibits polymerization. This observation suggests that sTREM2 could utilize this function to (at least partially) elicit its protective role in AD pathogenesis and highlights the need to understand regulation and production of sTREM2 by regulators such as MS4A4A [45].…”

“…For example, elevated levels of sTREM2 are associated with cognitive reserve in humans [10], and increasing sTREM2 in a mouse model of AD appears to ameliorate disease pathologies, including reducing amyloid plaque load and rescuing functional memory deficits [11]. Thus, understanding sTREM2 functions and how it is produced and regulated may shed new light on therapeutic targets [45]. Our data indicate that sTREM2 binds to mAβ42 and inhibits aggregation, which could be another route by which sTREM2 impedes AD development.…”

“…Soluble TREM2 (sTREM2) can be produced by proteolytic cleavage by ADAM10 and ADAM17 [6,7] or by alternate transcripts [8]. Its levels appear to be modulated by MS4A4A [45]. This sTREM2 can engage monomeric Aβ42 and prevent polymerization.…”

Peripheral nerve resident macrophages are microglia-like cells with tissue-specific programming

“…We identified 396 genes enriched in PNS macrophages and 180 genes enriched in CNS microglia (Supplementary Table 3). Since the upregulation of MS4A family and interferon-induced genes has been reported to characterize aged and neurodegenerative disease-associated microglia (6, 22, 23), we wondered if PNS macrophages expressed other genes associated with microglial activation. By cross-referencing published data, we determined the number of connections between disease-associated genes that were upregulated in activated microglia from aging, phagocytic, and neurodegenerative conditions and neural macrophage-enriched genes from either PNS macrophages or CNS microglia (Fig.…”

The Oft-Overlooked Massively Parallel Reporter Assay: Where, When, and Which Psychiatric Genetic Variants are Functional?

“…One challenge in parsing loci implicated in common variant association studies is that multiple variants in the region are equally statistically associated, and thus equally plausible functional mediators of risk. Indeed, in statistical genetics, repeating a GWAS or eQTL association analysis after conditioning on the lead SNP within a block often reveals one or more additional independent variants associated with traits or gene expression, respectively (e.g., (70,89,90)); in fact, nearly half (~8,000) of brain expressed genes have ≥ 1 conditional eQTL (91)Reporter assays have been used to systematically evaluate such linked sets of variants. One disease-oriented, small scale example used epigenomic data to identify 16 enhancers spread over a few hundred kilobases near the Ret gene, known to be downregulated in Hirschsprung's disease (failure of terminal colonic nerves to form in utero).…”