biostudies-literatureQiao WNIA NIH HHSNational Institute on Aging8https://www.ebi.ac.uk/biostudies/studies/S-EPMC9890893biostudies-literatureUnknown18(1)<h4>Background</h4>The rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimer's disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies.<h4>Methods</h4>We generated a novel Trem2 H157Y knock-in mouse model through CRISPR/Cas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, imMolecular neurodegenerationTrem2 H157Y increases soluble TREM2 production and reduces amyloid pathology.PMC9890893R37 AG027924RF1AG056130R01 AG066395RF1 AG056130R01AG066395RF1AG046205RF1 AG046205Meneses AChen KLiu CCZhu YBu GIkezu TCLi FKurti AMartens YAQiao WFryer JZhao NRosenberg CLKuchenbecker LADacquel MVCharlesworth CMMadden BJKnight JShue FChen YZhong JPandey AVanmaele LKfalseTrem2 H157Y increases soluble TREM2 production and reduces amyloid pathology.<h4>Background</h4>The rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimer's disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies.<h4>Methods</h4>We generated a novel Trem2 H157Y knock-in mouse model through CRISPR/Cas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, im2023-01-01T00:00:00Z2023 Jan2026-05-06T03:13:42.309Z2025-02-19T04:21:03.111ZS-EPMC98908933672120510.1186/s13024-023-00599-3