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

Dhandapani, R.; Neri, M.; Bernhard, M.; Brzak, I.; Schweizer, T.; Rudin, S.; Joller, S.; Berth, R.; Waldt, A.; Cuttat, R.; Naumann, U.; Gubser Keller, C.; Roma, G.; Feuerbach, D.; Shimshek, D. R.; Neumann, U.; Gasparini, F.; Galimberti, I.

doi:10.1101/2021.06.23.449405

bioRxiv · 10.1101/2021.06.23.449405

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

Dhandapani, R.·Neri, M.·Bernhard, M.·Brzak, I.·Schweizer, T.·Rudin, S.·Joller, S.·Berth, R.·Waldt, A.·Cuttat, R.·Naumann, U.·Gubser Keller, C.·Roma, G.·Feuerbach, D.·Shimshek, D. R.·Neumann, U.·Gasparini, F.·Galimberti, I.

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Abstract

TREM2 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 Alzheimers 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 A{beta} pathology in a mouse model of Alzheimers 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.

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Dhandapani, R., Neri, M., Bernhard, M., Brzak, I., Schweizer, T., Rudin, S., Joller, S., Berth, R., Waldt, A., Cuttat, R., Naumann, U., Gubser Keller, C., Roma, G., Feuerbach, D., Shimshek, D. R., Neumann, U., Gasparini, F., Galimberti, I.. 2021-06-23. Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease. https://doi.org/10.1101/2021.06.23.449405

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