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Alzheimer Disease / Alzheimer's Disease / Receptors, Immunologic · Journal article
Experimental Neurology · June 24, 2026
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This transgenic mouse study demonstrates that the TREM2 R47H variant produces a mild, functionally distinct microglial phenotype compared to complete TREM2 knockout, with alterations in ER stress and intracellular signalling genes rather than the broad microglial activation deficits seen in null mice. The findings support using R47H knockin rather than knockout models to study this Alzheimer's disease risk variant, but remain preclinical and require human validation.
Controlled transgenic mouse model comparison. Aged AppNL-F knock-in mice carrying humanized Trem2 R47H variant or complete Trem2 knockout.. Intervention: Humanized Trem2 R47H knock-in mutation on AppNL-F background. Compared with: Trem2 knockout mice and wild-type control mice.
Amyloid β 42 accumulation and dystrophic neurite formation increased in Trem2 KO mice at 18 or 24 months but not in Trem2 R47H KI mice Trem2 KO mice showed deficits in upregulation of microglial genes; Trem2 R47H KI mice showed response similar to control mice Differential gene expression analysis identified altered expressions of genes responsible for ER stress/unfolded protein response and intracellular signalling in Trem2 R47H KI mice
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This preclinical work refines understanding of how the TREM2 R47H risk variant mechanistically contributes to Alzheimer's disease pathology through altered microglial signalling, but clinical translation and validation in human brain tissue or living patients remain necessary before application to patient stratification or therapeutic targeting.
Mechanistic study in transgenic mice identifying divergent microglial phenotypes between R47H variant and null mutation; no clinical endpoint or human validation provided.
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Quoted from the source exactly as published.
This preclinical work refines understanding of how the TREM2 R47H risk variant mechanistically contributes to Alzheimer's disease pathology through altered microglial signalling, but clinical translation and validation in human brain tissue or living patients remain necessary before application to patient stratification or therapeutic targeting.
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The TREM2 R47H variant increases the risk of Alzheimer's disease (AD), yet its functional impact in aged mouse models remains incompletely understood. We generated a humanized Trem2 R47H knock-in (KI) line on the AppNL-F background and compared it with a Trem2 knockout (KO) line to assess the degree of TREM2 functional impairment. Accumulation of amyloid β 42 and formation of dystrophic neurites were increased in Trem2 KO mice but not in Trem2 R47H KI mice at 18 or 24 months. qPCR and transcriptomic analyses revealed Trem2 KO mice showed deficits in upregulation of microglial genes while Trem2 R47H KI mice showed a response similar to control mice. Differential gene expression analysis identified altered expressions of genes responsible for ER stress/unfolded protein response and intracellular signalling in Trem2 R47H KI mice. Among the differentially expressed genes, Pmel and Gpnmb were or tended to be downregulated in Trem2 R47H KI as well as in Trem2 KO mice indicating their involvement in AD pathogenesis. These results clearly indicate that the TREM2 R47H variant confers a mild, rather than null, effect on microglial alterations during AD development and that Trem2 R47H KI mice should be used to understand pathological mechanism elicited by TREM2. Further identification and characterization of genes differentially expressed in Trem2 R47H KI mice will provide important insights into how the TREM2 risk variant modulates Alzheimer's disease-related pathology.
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