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Joshi, Pranav; Riffel, Florian; Satoh, Kanayo; Enomoto, Masahiro; Qamar, Seema; Scheiblich, Hannah; Villacampa, Nadia; Kumar, Sathish; Theil, Sandra; Parhizkar, Samira; Haass, Christian; Heneka, Michael T.; Fraser, Paul E. and Walter, Jochen (2021): Differential interaction with TREM2 modulates microglial uptake of modified A beta species. In: Glia, Vol. 69, No. 12: pp. 2917-2932

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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 beta peptides (A beta). A beta peptides 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 A beta variants that could differ in their aggregation behavior and toxic properties. Here, we sought to assess whether post-translational modifications of A beta affect the interaction with TREM2. Biophysical and biochemical methods revealed that TREM2 preferentially interacts with oligomeric A beta, and that phosphorylation of A beta increases this interaction. Phosphorylation of A beta also affected the TREM2 dependent interaction and phagocytosis by primary microglia and in APP transgenic mouse models. Thus, TREM2 function is important for sensing phosphorylated A beta variants in distinct aggregation states and reduces the accumulation and deposition of these toxic A beta species in preclinical models of Alzheimer's disease.

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