Soluble TREM2 inhibits secondary nucleation of Aβ fibrillization and enhances cellular uptake of fibrillar Aβ

Author:

Belsare Ketaki D.1,Wu Haifan1,Mondal Dibyendu23,Bond Annalise4,Castillo Erika4ORCID,Jin Jia15,Jo Hyunil1,Roush Addison E.1,Pilla Kala Bharath23,Sali Andrej23ORCID,Condello Carlo46,DeGrado William F.1ORCID

Affiliation:

1. Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158

2. Department of Bioengineering and Therapeutic Sciences, Quantitative Biology Institute, University of California, San Francisco, CA 94158

3. Department of Pharmaceutical Chemistry, Quantitative Biology Institute, University of California, San Francisco, CA 94158

4. Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94158

5. College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, People’s Republic of China

6. Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158

Abstract

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.

Funder

NIH

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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