Other
23 Authors
- Cao S,
- Lin K,
- Poliani PL,
- Wang S,
- Colonna M,
- Nguyen K,
- Holtzman DM,
- Sudan R,
- Peng V,
- Chen Y,
- Hou J,
- Brown GD,
- Gilfillan S,
- Lei T,
- Cai Z,
- Brioschi S,
- Ellebedy AH,
- Zhou Y,
- Du S,
- Beatty WL,
- Rodrigues C,
- Cella M,
- Yuede CM
| First Author | Wang S | Year | 2022 |
| Journal | Cell | Volume | 185 |
| Issue | 22 | Pages | 4153-4169.e19 |
| PubMed ID | 36306735 | Mgi Jnum | J:333070 |
| Mgi Id | MGI:7384136 | Doi | 10.1016/j.cell.2022.09.033 |
| Citation | Wang S, et al. (2022) TREM2 drives microglia response to amyloid-beta via SYK-dependent and -independent pathways. Cell 185(22):4153-4169.e19 |
| abstractText | Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Abeta plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2(R47H) variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Abeta plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3beta-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Abeta involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2(R47H) allele, unveiling new options for AD immunotherapy. |
