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Differential interaction with TREM2 modulates microglial uptake of modified Aβspecies

Glia. 2021 Aug 24. doi: 10.1002/glia.24077. Epub ahead of print. PMID: 34427354.

Authors/Editors: Joshi P, Riffel F, Satoh K, Enomoto M, Qamar S, Scheiblich H, Villacampa N, Kumar S, Theil S, Parhizkar S, Haass C, Heneka MT, Fraser PE, St George-Hyslop P, Walter J.
Publication Date: 2021

09_joshi

Abstract

Rare coding variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) confer an increased risk for Alzheimer's disease (AD) characterized by the progressive accumulation of aggregated forms of amyloid βpeptides (Aβ). Aβpeptides are generated by proteolytic processing of the amyloid precursor protein (APP). Heterogeneity in proteolytic cleavages and additional post-translational modifications result in the production of several distinct Aβvariants that could differ in their aggregation behavior and toxic properties. Here, we sought to assess whether post-translational modifications of Aβaffect the interaction with TREM2. Biophysical and biochemical methods revealed that TREM2 preferentially interacts with oligomeric Aβ, and that phosphorylation of Aβ increases this interaction. Phosphorylation of Aβalso affected the TREM2 dependent interaction and phagocytosis by primary microglia and in APP transgenic mouse models. Thus, TREM2 function is important for sensing phosphorylated Aβvariants in distinct aggregation states and reduces the accumulation and deposition of these toxic Aβspecies in preclinical models of Alzheimer's disease.

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