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Cited by 68Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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Belsare, Ketaki D., Wu, Haifan, Mondal, Dibyendu, Bond, Annalise, Castillo, Erika, Jin, Jia, Jo, Hyunil, Roush, Addison E. +4 more·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2114486119PMC PMC8812518
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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.

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  • Increased sTREM2 inhibits fibrillization of Aβ peptides, increases uptake of Aβ fibrils into microglial cells, and attenuates cognitive and clinical decline in AD patients and AD mouse models.

    “Epidemiologic study of AD patients revealed that increased sTREM2 was shown to be beneficial: it can inhibit the fibrillization of Aβ peptides, increase the uptake of Aβ fibrils into microglial cells,235 and attenuate cognitive and clinical decline in AD patients and AD mouse models.236,237”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [235]

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Authors
Belsare, K. D., Wu, H., Mondal, D., Bond, A., Castillo, E., Jin, J., Jo, H., Roush, A. E., Pilla, K. B., Sali, A., Condello, C., & DeGrado, W. F.
Affiliations
  • University of California, San Francisco (US)
  • Zhejiang Sci-Tech University (CN)
  • Department of Bioengineering and Therapeutic Sciences, Quantitative Biology Institute, University of California, San Francisco, CA 94158
Corresponding author
  • Condello, Carlo
  • DeGrado, William F.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-01-26
Volume
119
Issue
5
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2114486119
PMC
PMC8812518
OpenAlex
W4210680552
Cited by
68
References
13
Citations by year
2026: 16 · 2025: 14 · 2024: 16 · 2023: 19 · 2022: 3
FWCI
8.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
NIH (P30AG06242, RF1AG061874, P01AG002132, R01GM083960, P41GM109824)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
soluble TREM2, secondary nucleation, amyloid-beta uptake, Alzheimer's disease, microglia, primary nucleation, cross-linking mass spectrometry
MeSH terms
Alzheimer Disease, Amyloid, Animals, Humans, Kinetics, Membrane Glycoproteins, Mutation, Peptide Fragments, Receptors, Immunologic, Amyloid beta-Peptides, tau Proteins, Microglia, Mice, Plaque, Amyloid

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