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Sustained TREM2 stabilization accelerates microglia heterogeneity and Aβ pathology in a mouse model of Alzheimer’s disease

Authors :
Dhandapani R
Stefanie Joller
Marilisa Neri
Ivan Galimberti
Annick Waldt
Rachel Cuttat
Irena Brzak
Dominik Feuerbach
Rudin S
Guglielmo Roma
Derya R. Shimshek
Tatjana Schweizer
Ulf Neumann
Berth R
Caroline Gubser Keller
Mario Bernhard
Ulrike Naumann
Fabrizio Gasparini
Publication Year :
2021
Publisher :
Cold Spring Harbor Laboratory, 2021.

Abstract

SummaryTREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimer’s disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. We generated a transgenic mouse model of reduced TREM2 shedding (Trem2-IPD) through amino acid substitution of ADAM-protease recognition site. We found that Trem2-IPD mice displayed increased TREM2 cell surface receptor load, survival and function in myeloid cells. Using single cell transcriptomic profiling of mouse cortex we show that sustained TREM2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Aβ pathology in a mouse model of Alzheimer’s disease. Our data indicate that reduction of TREM2 proteolytic cleavage aggravates neuroinflammation during the course of AD pathology suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........ebf27af7c06d253b6e85e60ed8e8e2a7
Full Text :
https://doi.org/10.1101/2021.06.23.449405