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 ? (A?) accumulation in a mouse model of Alzheimer-type A? pathology. sTLR5Fc binds to oligomeric and fibrillar A? with high affinity, forms complexes with A?, and blocks A? toxicity. Oligomeric and fibrillar A? 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 A?-selective class of biotherapy in AD.

SUBMITTER: Chakrabarty P 

PROVIDER: S-EPMC6122970 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature