| First Author | Liu S | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 3 | Pages | 1098-107 |
| PubMed ID | 22198949 | Mgi Jnum | J:180762 |
| Mgi Id | MGI:5307186 | Doi | 10.4049/jimmunol.1101121 |
| Citation | Liu S, et al. (2012) TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation. J Immunol 188(3):1098-107 |
| abstractText | Microglia activated by extracellularly deposited amyloid beta peptide (Abeta) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Abeta via phagocytosis. TLRs are associated with Abeta-induced microglial inflammatory activation and Abeta internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Abeta (Abeta42). TLR2 deficiency reduced Abeta42-triggered inflammatory activation but enhanced Abeta phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Abeta42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Abeta42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Abeta to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis. |
