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, Institute for Systems Biology, Seattle, WA.
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 Medway
Christopher Janus
Hong-Dong Li, Institute for Systems Biology, Seattle, WA.
Dennis W Dickson
Benoit I Giasson
Nathan D Price, Institute for Systems Biology, Seattle, WA.
Steven G Younkin
Nilüfer Ertekin-Taner
Todd E Golde


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.