Chakrabarty P, Li A, Ladd TB, Strickland MR, Koller EJ, Burgess JD, Funk CC, Cruz PE, Allen M, Yaroshenko M, Wang X, Younkin C, Reddy J, Lohrer B, Mehrke L, Moore BD, Liu X, Ceballos-Diaz C, Rosario AM, Medway C, Janus C, Li HD, Dickson DW, Giasson BI, Price ND, Younkin SG, Ertekin-Taner N, Golde TE. TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease. J Exp Med. 2018 Sep 3;215(9):2247-2264. PubMed.
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Here the authors did a systematic analysis of Toll-like receptor (TLR) gene expression in the brains of AD patients versus controls and they found a significant increase in specific members of this family, including TLR2, 4, and 5. To explore the role of these receptors in the brain of a mouse model of AD, they generated rAAV2 plasmid constructs for chicken β-actin promoter–driven ectodomains of TLRs 2, 4, and 5 with a C terminus molecular tag consisting of FLAG, streptavidin, and 6X-histidine. While TLR4 and 5 gene delivery caused a robust decrease of the amyloid load, similar delivery of TLR2 had no such effect. To further investigate whether soluble ectodomains of TLRs can be developed into immunotherapeutics, they created functionalized versions of sTLR4 and sTLR5 by adding human IgG4 Fc domain to the C terminus of the sTLR. This approach was only significant for sTLR5, which was further investigated.
In summary, they demonstrate that sTLR5/sTLR5Fc acts as a novel anti-Aβ immunotherapeutic agent in mice in both preventive and therapeutic paradigms. The efficacy for reducing amyloid loads and blocking toxicity can be attributed to the direct binding of sTLR5 ectodomain to Aβ. Further sTLR5Fc blocks Aβ toxicity in primary neuroglial cultures, and sTLR5Fc directly facilitates microglial uptake of Aβ in vitro.
Although quite interesting and adding more evidence that innate immune receptors are clearly the angle to improve Aβ clearance by microglia and circulating monocytes at the luminal side the blood-brain barrier (BBB), such effects were neither associated with cognitive improvement nor any changes in markers of synaptic functions. As for most studies on TREM2, the lack of correlation between Aβ clearance and cognitive and synaptic functions is always a major drawback that further weakens the amyloid hypothesis as being a key immunotherapy target for AD. Many reasons may explain this, such as a delivery system that is not optimal across the whole CNS or for microglia in vivo—or that the behavior analyses performed or the animal models used were not optimal for these analyses. The hope is that such reasons explain the lack of correlation between Aβ clearance and cognitive and synaptic functions, otherwise all the elegant biochemical work done on TLR5 means very little physiologically.
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