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

The Journal of Experimental Medicine
Paramita ChakrabartyTodd E Golde

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.

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Citations

Mar 11, 2019·Molecular Neurobiology·Marisol Herrera-RiveroMichael T Heneka
Feb 13, 2019·International Journal of Molecular Sciences·Michiel Van BulckJose A Morales-Garcia
Aug 10, 2019·BioMed Research International·Henriette R FrederiksenKristine Freude
Sep 12, 2020·Acta Neuropathologica Communications·Masataka IfukuSeija Lehnardt
Dec 17, 2020·Frontiers in Molecular Neuroscience·Madeleine R BrownEric W Hewitt
Mar 19, 2020·Cell Reports·Lea L FrikerMichael T Heneka
May 1, 2021·International Journal of Molecular Sciences·Maryam Mahjoubin-TehranAmirhossein Sahebkar
Jun 16, 2021·Life Science Alliance·Karen N McFarlandTodd E Golde

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Methods Mentioned

BETA
transgenic
RNAseq
tandem affinity purification
transfection
immunoprecipitation assay
biolayer interferometry
ELISA
biosensors
Chip
genotyping

Software Mentioned

SigmaStat
NanoString
Color Thresholder
Actimetrics
Fortebio Data Analysis
ImageJ
Aperio
DIRAC
- package
Fiji

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