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TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease.

Chakrabarty P., Li A., Ladd T.B., Strickland M.R., Koller E.J., Burgess J.D., Funk C.C., Cruz P.E., Allen M., Yaroshenko M., Wang X., Younkin C., Reddy J., Lohrer B., Mehrke L., Moore B.D., Liu X., Ceballos-Diaz C., Rosario A.M., Medway C., Janus C., Li H.D., Dickson D.W., Giasson B.I., Price N.D., Younkin S.G., Ertekin-Taner N., Golde T.E.

There is considerable interest in harnessing innate immunity to treat Alzheimer's disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity. Oligomeric and fibrillar Aβ modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling. Genetic analysis shows that rare protein coding variants in human TLR5 may be associated with a reduced risk of AD. Further, transcriptome analysis shows altered TLR gene expression in human AD. Collectively, our data suggest that TLR5 decoy receptor-based biologics represent a novel and safe Aβ-selective class of biotherapy in AD.

J Exp Med 215:2247-2264(2018) [PubMed] [Europe PMC]

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