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

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The Journal of experimental medicine, ISSN: 1540-9538, Vol: 215, Issue: 9, Page: 2247-2264

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10.1084/jem.20180484; 10.3410/f.733877199.793551421
Chakrabarty, Paramita; Li, Andrew; Ladd, Thomas B; Strickland, Michael R; Koller, Emily J; Burgess, Jeremy D; Funk, Cory C; Cruz, Pedro E; Allen, Mariet; Yaroshenko, Mariya; Wang, Xue; Younkin, Curtis; Reddy, Joseph; Lohrer, Benjamin; Mehrke, Leonie; Moore, Brenda D; Liu, Xuefei; Ceballos-Diaz, Carolina; Rosario, Awilda M; Medway, Christopher; Janus, Christopher; Li, Hong-Dong; Dickson, Dennis W; Giasson, Benoit I; Price, Nathan D; Younkin, Steven G; Ertekin-Taner, Nilüfer; Golde, Todd E Show More Hide
Rockefeller University Press; Faculty of 1000, Ltd.
Medicine; Immunology and Microbiology; Geriatrics; Neurology
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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.