Wenhui Qiao, Yixing Chen, Jun Zhong, Benjamin J Madden, Cristine M Charlesworth, Yuka A Martens, Chia-Chen Liu, Joshua Knight, Tadafumi C Ikezu, Kurti Aishe, Yiyang Zhu, Axel Meneses, Cassandra L Rosenberg, Lindsey A Kuchenbecker, Lucy K Vanmaele, Fuyao Li, Kai Chen, Francis Shue, Maxwell V Dacquel, John Fryer, Akhilesh Pandey, Na Zhao, Guojun Bu
BACKGROUND: 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. METHODS: 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, immunofluorescent staining, in vivo micro-dialysis, and cortical bulk RNA sequencing...
January 31, 2023: Molecular Neurodegeneration