@article{dde8ff88d9f24a2d86c70e203aea997f,
title = "TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease",
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.",
author = "Paramita Chakrabarty and Andrew Li and Ladd, {Thomas B.} and Strickland, {Michael R.} and Koller, {Emily J.} and Burgess, {Jeremy D.} and Funk, {Cory C.} and Cruz, {Pedro E.} and Mariet Allen and Mariya Yaroshenko and Xue Wang and Curtis Younkin and Joseph Reddy and Benjamin Lohrer and Leonie Mehrke and Moore, {Brenda D.} and Xuefei Liu and Carolina Ceballos‑Diaz and Rosario, {Awilda M.} and Christopher Medway and Christopher Janus and Li, {Hong Dong} and Dickson, {Dennis W.} and Giasson, {Benoit I.} and Price, {Nathan D.} and Younkin, {Steven G.} and Nil{\"u}fer Ertekin‑Taner and Golde, {Todd E.}",
note = "Funding Information: The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026, National Brain and Tissue Resource for Parkinson{\textquoteright}s Disease and Related Disorders), the National Institute on Aging (P30 AG19610, Arizona Alzheimer{\textquoteright}s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer{\textquoteright}s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson{\textquoteright}s Disease Consortium), and the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research. This work was supported by the National Institutes of Health/National Institute on Aging (U01 AG046139 to T.E. Golde, N.D. Price, and N. Ertekin-Taner and R01 AG018454 to T.E. Golde) and a BrightFocus Foundation Fellowship (P. Chakrabarty). Publisher Copyright: {\textcopyright} 2018 Chakrabarty et al.",
year = "2018",
doi = "10.1084/jem.20180484",
language = "English (US)",
volume = "215",
pages = "2247--2264",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "9",
}