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

Paramita Chakrabarty, Andrew Li, Thomas B. Ladd, Michael R. Strickland, Emily J. Koller, Jeremy D. Burgess, Cory C. Funk, Pedro E. Cruz, Mariet Allen, Mariya Yaroshenko, Xue Wang, Curtis Younkin, Joseph Reddy, Benjamin Lohrer, Leonie Mehrke, Brenda D. Moore, Xuefei Liu, Carolina Ceballos‑Diaz, Awilda M. Rosario, Christopher MedwayChristopher Janus, Hong Dong Li, Dennis W Dickson, Benoit I. Giasson, Nathan D. Price, Steven G Younkin, Nilufer Taner, Todd E. Golde

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2247-2264
Number of pages18
JournalJournal of Experimental Medicine
Volume215
Issue number9
DOIs
StatePublished - Jan 1 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    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., ... Golde, T. E. (2018). TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease. Journal of Experimental Medicine, 215(9), 2247-2264. https://doi.org/10.1084/jem.20180484