TLR5 Decoy Receptor As a Novel Anti-amyloid Therapeutic for Alzheimer's Disease

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2018 Aug 31

PMID 30158114

Citations 33

Authors

Paramita Chakrabarty

Andrew Li

Thomas B Ladd

Michael R Strickland

Emily J Koller

Jeremy D Burgess

Cory C Funk

Pedro E Cruz

Mariet Allen

Mariya Yaroshenko

Xue Wang

Curtis Younkin

Joseph Reddy

Benjamin Lohrer

Leonie Mehrke

Brenda D Moore

Xuefei Liu

Carolina Ceballos-Diaz

Awilda M Rosario

Christopher Medway

Christopher Janus

Hong-Dong Li

Dennis W Dickson

Benoit I Giasson

Nathan D Price

Steven G Younkin

Nilufer Ertekin-Taner

Todd E Golde

Affiliations

Soon will be listed here.

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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References

Hanna A, Iremonger K, Das P, Dickson D, Golde T, Janus C . Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis. Alzheimers Res Ther. 2012; 4(3):21. PMC: 3506935. DOI: 10.1186/alzrt124. View

Heneka M, Golenbock D, Latz E . Innate immunity in Alzheimer's disease. Nat Immunol. 2015; 16(3):229-36. DOI: 10.1038/ni.3102. View

Matarin M, Salih D, Yasvoina M, Cummings D, Guelfi S, Liu W . A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep. 2015; 10(4):633-44. DOI: 10.1016/j.celrep.2014.12.041. View

Lein E, Hawrylycz M, Ao N, Ayres M, Bensinger A, Bernard A . Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2006; 445(7124):168-76. DOI: 10.1038/nature05453. View

Henrick B, Yao X, Taha A, German J, Rosenthal K . Insights into Soluble Toll-Like Receptor 2 as a Downregulator of Virally Induced Inflammation. Front Immunol. 2016; 7:291. PMC: 4969314. DOI: 10.3389/fimmu.2016.00291. View

Price A, Patterson N, Plenge R, Weinblatt M, Shadick N, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38(8):904-9. DOI: 10.1038/ng1847. View

Atwal J, Chen Y, Chiu C, Mortensen D, Meilandt W, Liu Y . A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo. Sci Transl Med. 2011; 3(84):84ra43. DOI: 10.1126/scitranslmed.3002254. View

Heppner F, Ransohoff R, Becher B . Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015; 16(6):358-72. DOI: 10.1038/nrn3880. View

Huang C . Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology. Curr Opin Biotechnol. 2009; 20(6):692-9. DOI: 10.1016/j.copbio.2009.10.010. View

10.

Grossman S, Andersen K, Shlyakhter I, Tabrizi S, Winnicki S, Yen A . Identifying recent adaptations in large-scale genomic data. Cell. 2013; 152(4):703-13. PMC: 3674781. DOI: 10.1016/j.cell.2013.01.035. View

11.

Reed-Geaghan E, Savage J, Hise A, Landreth G . CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci. 2009; 29(38):11982-92. PMC: 2778845. DOI: 10.1523/JNEUROSCI.3158-09.2009. View

12.

Chakrabarty P, Rosario A, Cruz P, Siemienski Z, Ceballos-Diaz C, Crosby K . Capsid serotype and timing of injection determines AAV transduction in the neonatal mice brain. PLoS One. 2013; 8(6):e67680. PMC: 3692458. DOI: 10.1371/journal.pone.0067680. View

13.

Chakrabarty P, Li A, Ceballos-Diaz C, Eddy J, Funk C, Moore B . IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 2015; 85(3):519-33. PMC: 4320003. DOI: 10.1016/j.neuron.2014.11.020. View

14.

Saykin A, Shen L, Yao X, Kim S, Nho K, Risacher S . Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans. Alzheimers Dement. 2015; 11(7):792-814. PMC: 4510473. DOI: 10.1016/j.jalz.2015.05.009. View

15.

Karch C, Goate A . Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2014; 77(1):43-51. PMC: 4234692. DOI: 10.1016/j.biopsych.2014.05.006. View

16.

Thakker D, Weatherspoon M, Harrison J, Keene T, Lane D, Kaemmerer W . Intracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice. Proc Natl Acad Sci U S A. 2009; 106(11):4501-6. PMC: 2647980. DOI: 10.1073/pnas.0813404106. View

17.

Kawai T, Akira S . Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011; 34(5):637-50. DOI: 10.1016/j.immuni.2011.05.006. View

18.

Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello A, Antoniello K . An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci. 2012; 32(28):9677-89. PMC: 6622286. DOI: 10.1523/JNEUROSCI.4742-11.2012. View

19.

Levites Y, Das P, Price R, Rochette M, Kostura L, McGowan E . Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest. 2005; 116(1):193-201. PMC: 1307561. DOI: 10.1172/JCI25410. View

20.

Hansen K, Irizarry R, Wu Z . Removing technical variability in RNA-seq data using conditional quantile normalization. Biostatistics. 2012; 13(2):204-16. PMC: 3297825. DOI: 10.1093/biostatistics/kxr054. View