Using an innovative approach, scientists move one step closer to a treatment for Alzheimer's. Learning how to tame the brain's immune sys...
TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease.
- Citation data:
The Journal of experimental medicine, ISSN: 1540-9538, Vol: 215, Issue: 9, Page: 2247-2264
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- Repository URL:
- https://digitalcommons.psjhealth.org/publications/603; https://digitalcommons.psjhealth.org/publications/602
- 10.1084/jem.20180484; 10.3410/f.733877199.793551421
- 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.