Association of TREM1 rs2234246 with miR-138-5p-dependent reporter regulation, TREM1 expression, and hippocampal volume in Alzheimer’s disease

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder in which neuroinflammation contributes to disease pathogenesis. Triggering receptor expressed on myeloid cells 1 (TREM1) has been implicated in inflammatory responses, and the functional polymorphism rs2234246, located in the 3′-untranslated region (UTR) of TREM1, has been associated with TREM1 expression and brain amyloid deposition. We hypothesized that rs2234246 regulates TREM1 expression through microRNA (miR)-138-5p and is associated with AD-related neurodegenerative changes. To test this hypothesis, we performed SNP functional analysis, dual-luciferase reporter assays, peripheral blood expression analyses o f membrane form ( mbTREM1 ), soluble form ( TREM1sv ), and miR-138-5p, and magnetic resonance imaging (MRI)-based hippocampal volumetric analyses. The rs2234246 A allele was associated with increased mbTREM1 mRNA expression but not TREM1sv expression. Dual-luciferase reporter assays demonstrated allele-dependent reporter repression consistent with an interaction between miR-138-5p and the TREM1 3′-UTR containing the A allele. In patients with AD, plasma TREM-1 protein concentration and miR-138-5p expression were significantly increased, whereas TREM1sv expression was significantly decreased. Furthermore, the rs2234246 A allele was associated with reduced right hippocampal volume in patients with AD. These findings provide complementary evidence of allele-dependent reporter regulation involving miR-138-5p, altered peripheral TREM1-related expression in AD, and an exploratory association between rs2234246 and right hippocampal volume. Further studies are required to clarify the biological relationships among these findings and their relevance to AD pathogenesis.