Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation

J Biol Chem. 2021 Jan-Jun:296:100631. doi: 10.1016/j.jbc.2021.100631. Epub 2021 Apr 3.

Abstract

TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids and Aβ and inducing an innate immune response. Missense mutations (e.g., R47H) of TREM2 increase risk of Alzheimer's disease (AD). The soluble ectodomain of wild-type TREM2 (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that Aβ oligomers bind to cellular TREM2, inducing shedding of the sTREM2 domain. Wild-type sTREM2 bound to Aβ oligomers (measured by single-molecule imaging, dot blots, and Bio-Layer Interferometry) inhibited Aβ oligomerization and disaggregated preformed Aβ oligomers and protofibrils (measured by transmission electron microscopy, dot blots, and size-exclusion chromatography). Wild-type sTREM2 also inhibited Aβ fibrillization (measured by imaging and thioflavin T fluorescence) and blocked Aβ-induced neurotoxicity (measured by permeabilization of artificial membranes and by loss of neurons in primary neuronal-glial cocultures). In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aβ but rather promotes Aβ protofibril formation and neurotoxicity. Thus, in addition to inducing an immune response, wild-type TREM2 may protect against amyloid pathology by the Aβ-induced release of sTREM2, which blocks Aβ aggregation and neurotoxicity. In contrast, R47H sTREM2 promotes Aβ aggregation into protofibril that may be toxic to neurons. These findings may explain how wild-type sTREM2 apparently protects against AD in vivo and why a single copy of the R47H variant gene is associated with increased AD risk.

Keywords: Alzheimer's disease; TREM2; amyloid beta; microglia; neurotoxicity; oligomers; sTREM2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease
  • Amyloid / chemistry*
  • Amyloid / metabolism
  • Amyloid beta-Peptides / chemistry*
  • Animals
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Knockout
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Mutation*
  • Neurons / metabolism
  • Neurons / pathology*
  • Neurotoxicity Syndromes / etiology
  • Neurotoxicity Syndromes / pathology*
  • Receptors, Immunologic / physiology*

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Membrane Glycoproteins
  • Mutant Proteins
  • Receptors, Immunologic
  • Trem2 protein, mouse