Citations 1
TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease
Chakrabarty, Paramita , Li, Andrew, Ladd, Thomas B., Strickland, Michael R. , Koller, Emily J., Burgess, Jeremy D. , Funk, Cory C. , Allen, Mariet , Yaroshenko, Mariya, Wang, Xue , Younkin, Curtis, Reddy, Joseph S. , Lohrer, Benjamin , Mehrke, Leonie S. , Moore, Brenda D. , Ceballos‐Diaz, Carolina, Rosario, Awilda M., Medway, Christopher, Janus, Christopher, Li, Hongdong , Giasson, Benoit I. , Price, Nathan D. , Younkin, Steven G. , Ertekin‐Taner, Nilüfer , Golde, Todd E. , Reddy, Joseph , Mehrke, Leonie, Price, Nathan D , Golde, Todd E , Cruz, Pedro E. , Wang, Xue, Liu, Xuefei , Li, Hong-Dong, Dickson, Dennis W.
Journal of Experimental Medicine | August 29, 2018 | Volume: 215 | Issue: 9 | Pages: 2247-2264
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.