Open AccessSoluble TREM2 inhibits secondary nucleation of Aβ fibrillization and enhances cellular uptake of fibrillar Aβ
Author(s) -
Ketaki Belsare,
Haifan Wu,
Dibyendu Mondal,
Annalise Bond,
Erika Castillo,
Junhong Jin,
Hyunil Jo,
Addison E Roush,
Kala Bharath Pilla,
Andrej Šali,
Carlo Condello,
William F. DeGrado
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2114486119
Subject(s) - ectodomain , fibril , chemistry , trem2 , biophysics , transmembrane protein , mutant , nucleation , biochemistry , plasma protein binding , receptor , microbiology and biotechnology , biology , myeloid cells , organic chemistry , gene
Significance Mutations in a microglial protein, TREM2, represents a risk for Alzheimer’s disease (AD). We show that the soluble form of TREM2, sTREM2, can bind and inhibit fibrillization of Aβ peptides. sTREM2 increases uptake of Aβ fibrils into microglial and neuroglioma cell lines. Contrastingly, mutation R47H was found to have little effect on fibril nucleation and binding, but decreased uptake and functional responses. Our findings using integrative molecular modeling based on cross-linking mass spectrometry data for WT sTREM2–Aβ fibril complex demonstrate that TREM2 has at least two ligand-binding surfaces: one binding Aβ fibrils and the other anionic polyvalent ligands. R47H mutation lies on the latter surface. These findings inform mechanisms by which TREM2 modulates key processes in AD progression.