| First Author | Vilalta A | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100631 | PubMed ID | 33823153 |
| Mgi Jnum | J:308299 | Mgi Id | MGI:6707274 |
| Doi | 10.1016/j.jbc.2021.100631 | Citation | Vilalta A, et al. (2021) Wild-type sTREM2 blocks Abeta aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Abeta aggregation. J Biol Chem :100631 |
| abstractText | TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids and Abeta, 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 Abeta oligomers bind to cellular TREM2, inducing shedding of the sTREM2 domain. Wild-type sTREM2 bound to Abeta oligomers (measured by single-molecule imaging, dot blots and Bio-Layer Interferometry), inhibited Abeta oligomerization and disaggregated preformed Abeta oligomers and protofibrils (measured by transmission electron microscopy, dot blots and size exclusion chromatography). Wild-type sTREM2 also inhibited Abeta fibrillization (measured by imaging and thioflavin T fluorescence) and blocked Abeta-induced neurotoxicity (measured by permeabilization of artificial membranes and by loss of neurons in primary neuronal-glial co-cultures). In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Abeta, but rather promotes Abeta protofibril formation and neurotoxicity. Thus, in addition to inducing an immune response, wild-type TREM2 may protect against amyloid pathology by the Abeta-induced release of sTREM2, which blocks Abeta aggregation and neurotoxicity. In contrast, R47H sTREM2 promotes Abeta 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. |
