Intramembrane attenuation of the TLR4-TLR6 dimer impairs receptor assembly and reduces microglia-mediated neurodegeneration.
Recently, a single study revealed a new complex composed of Toll-like receptor 4 (TLR4), TLR6, and CD36 induced by fibrillary Aβ peptides, the hallmark of Alzheimer's disease. Unlike TLRs located on the plasma membrane that dimerize on the membrane after ligand binding to their extracellular domain, the TLR4-TLR6-CD36 complex assembly has been suggested to be induced by intracellular signals from CD36, similar to integrin inside-out signaling. However, the assembly site of TLR4-TLR6-CD36 and the domains participating in Aβ-induced signaling is still unknown. By interfering with TLR4-TLR6 dimerization using a TLR4-derived peptide, we show that receptor assembly is abrogated within the plasma membrane. Furthermore, we reveal that the transmembrane domains of TLR4 and TLR6 have an essential role in receptor dimerization and activation. Inhibition of TLR4-TLR6 assembly was associated with reduced secretion of proinflammatory mediators from microglia cells, ultimately rescuing neurons from death. Our findings support TLR4-TLR6 dimerization induced by Aβ. Moreover, we shed new light on TLR4-TLR6 assembly and localization and show the potential of inhibiting TLR4-TLR6 dimerization as a treatment of Alzheimer's disease.
['Shmuel-Galia|Liraz|L|', 'Klug|Yoel|Y|', 'Porat|Ziv|Z|', 'Charni|Meital|M|', 'Zarmi|Batya|B|', 'Shai|Yechiel|Y|']
D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D000818:Animals D018955:CD36 Antigens D002460:Cell Line D002470:Cell Survival D002478:Cells, Cultured D018920:Coculture Techniques D031541:Fluorescence Resonance Energy Transfer D047468:Immunoprecipitation D008024:Ligands D051379:Mice D017628:Microglia D009419:Nerve Tissue Proteins D009474:Neurons D018697:Nootropic Agents D010446:Peptide Fragments D055503:Protein Multimerization D011993:Recombinant Fusion Proteins D011994:Recombinant Proteins D051197:Toll-Like Receptor 4 D051216:Toll-Like Receptor 6
toll-like receptor TLR4 TLR6 CD36 microglia Alzheimer disease amyloid-β inflammation neurodegenerative disease neuroinflammation