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

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; Nilüfer Ertekin‑Taner; Todd E. Golde

doi:10.1084/jem.20180484

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

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 MedwayChristopher Janus, Hong Dong Li, Dennis W. Dickson, Benoit I. Giasson, Nathan D. Price, Steven G. Younkin, Nilüfer Ertekin‑Taner, Todd E. Golde

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2247-2264
Number of pages	18
Journal	Journal of Experimental Medicine
Volume	215
Issue number	9
DOIs	https://doi.org/10.1084/jem.20180484
State	Published - 2018

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Chakrabarty, P., Li, A., Ladd, T. B., Strickland, M. R., Koller, E. J., Burgess, J. D., Funk, C. C., Cruz, P. E., Allen, M., Yaroshenko, M., Wang, X., Younkin, C., Reddy, J., Lohrer, B., Mehrke, L., Moore, B. D., Liu, X., Ceballos‑Diaz, C., Rosario, A. M., ... Golde, T. E. (2018). TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease. Journal of Experimental Medicine, 215(9), 2247-2264. https://doi.org/10.1084/jem.20180484

Chakrabarty, P, Li, A, Ladd, TB, Strickland, MR, Koller, EJ, Burgess, JD, Funk, CC, Cruz, PE, Allen, M, Yaroshenko, M, Wang, X, Younkin, C, Reddy, J, Lohrer, B, Mehrke, L, Moore, BD, Liu, X, Ceballos‑Diaz, C, Rosario, AM, Medway, C, Janus, C, Li, HD, Dickson, DW, Giasson, BI, Price, ND, Younkin, SG , Ertekin‑Taner, N & Golde, TE 2018, 'TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease', Journal of Experimental Medicine, vol. 215, no. 9, pp. 2247-2264. https://doi.org/10.1084/jem.20180484

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title = "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 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.",

author = "Paramita Chakrabarty and Andrew Li and Ladd, {Thomas B.} and Strickland, {Michael R.} and Koller, {Emily J.} and Burgess, {Jeremy D.} and Funk, {Cory C.} and Cruz, {Pedro E.} and Mariet Allen and Mariya Yaroshenko and Xue Wang and Curtis Younkin and Joseph Reddy and Benjamin Lohrer and Leonie Mehrke and Moore, {Brenda D.} and Xuefei Liu and Carolina Ceballos‑Diaz and Rosario, {Awilda M.} and Christopher Medway and Christopher Janus and Li, {Hong Dong} and Dickson, {Dennis W.} and Giasson, {Benoit I.} and Price, {Nathan D.} and Younkin, {Steven G.} and Nil{\"u}fer Ertekin‑Taner and Golde, {Todd E.}",

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year = "2018",

doi = "10.1084/jem.20180484",

language = "English (US)",

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AU - Chakrabarty, Paramita

AU - Li, Andrew

AU - Ladd, Thomas B.

AU - Strickland, Michael R.

AU - Koller, Emily J.

AU - Burgess, Jeremy D.

AU - Funk, Cory C.

AU - Cruz, Pedro E.

AU - Allen, Mariet

AU - Yaroshenko, Mariya

AU - Wang, Xue

AU - Younkin, Curtis

AU - Reddy, Joseph

AU - Lohrer, Benjamin

AU - Mehrke, Leonie

AU - Moore, Brenda D.

AU - Liu, Xuefei

AU - Ceballos‑Diaz, Carolina

AU - Rosario, Awilda M.

AU - Medway, Christopher

AU - Janus, Christopher

AU - Li, Hong Dong

AU - Dickson, Dennis W.

AU - Giasson, Benoit I.

AU - Price, Nathan D.

AU - Younkin, Steven G.

AU - Ertekin‑Taner, Nilüfer

AU - Golde, Todd E.

PY - 2018

Y1 - 2018

N2 - 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.

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

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