Selective disruption of TLR2/MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology

Suresh B Rangasamy, Malabendu Jana, Avik Roy, Grant T Corbett, Madhuchhanda Kundu, Sujyoti Chandra, Susanta Mondal, Sridevi Dasarathi, Elliott J Mufson, Rama K Mishra, Chi-Hao Luan, David A Bennett, Kalipada Pahan

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Induction of TLR2 activation depends on its association with adapter protein MyD88. We have found that levels of TLR2 and MyD88 are elevated in the hippocampus and cortex of Alzheimer's disease (AD) patients and 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, but not other TLRs. Interestingly, wild type (wt) TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, double-stranded RNA, bacterial lipopolysaccharide, flagellin, and CpG DNA. After intranasal administration, wtTIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, wtTIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to 5XFAD mice, wtTIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of activated status of one component of the innate immune system by wtTIDM peptide may be beneficial in AD as well as other disorders in which TLR2-MyD88 signaling plays a role in disease pathogenesis.

Original languageEnglish (US)
JournalThe Journal of clinical investigation
DOIs
StateE-pub ahead of print - Jul 10 2018

Fingerprint

Pathology
Inflammation
Peptides
Alzheimer Disease
Hippocampus
Myeloid Differentiation Factor 88
1-Methyl-4-phenylpyridinium
Flagellin
Intranasal Administration
Experimental Arthritis
Double-Stranded RNA
Autoimmune Experimental Encephalomyelitis
Neuroglia
Lipopolysaccharides
Immune System
Learning
Apoptosis
DNA
Therapeutics

Cite this

Rangasamy, Suresh B ; Jana, Malabendu ; Roy, Avik ; Corbett, Grant T ; Kundu, Madhuchhanda ; Chandra, Sujyoti ; Mondal, Susanta ; Dasarathi, Sridevi ; Mufson, Elliott J ; Mishra, Rama K ; Luan, Chi-Hao ; Bennett, David A ; Pahan, Kalipada. / Selective disruption of TLR2/MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology. In: The Journal of clinical investigation. 2018.
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title = "Selective disruption of TLR2/MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology",
abstract = "Induction of TLR2 activation depends on its association with adapter protein MyD88. We have found that levels of TLR2 and MyD88 are elevated in the hippocampus and cortex of Alzheimer's disease (AD) patients and 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, but not other TLRs. Interestingly, wild type (wt) TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, double-stranded RNA, bacterial lipopolysaccharide, flagellin, and CpG DNA. After intranasal administration, wtTIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, wtTIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to 5XFAD mice, wtTIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of activated status of one component of the innate immune system by wtTIDM peptide may be beneficial in AD as well as other disorders in which TLR2-MyD88 signaling plays a role in disease pathogenesis.",
author = "Rangasamy, {Suresh B} and Malabendu Jana and Avik Roy and Corbett, {Grant T} and Madhuchhanda Kundu and Sujyoti Chandra and Susanta Mondal and Sridevi Dasarathi and Mufson, {Elliott J} and Mishra, {Rama K} and Chi-Hao Luan and Bennett, {David A} and Kalipada Pahan",
year = "2018",
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Rangasamy, SB, Jana, M, Roy, A, Corbett, GT, Kundu, M, Chandra, S, Mondal, S, Dasarathi, S, Mufson, EJ, Mishra, RK, Luan, C-H, Bennett, DA & Pahan, K 2018, 'Selective disruption of TLR2/MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology' The Journal of clinical investigation. https://doi.org/10.1172/JCI96209

Selective disruption of TLR2/MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology. / Rangasamy, Suresh B; Jana, Malabendu; Roy, Avik; Corbett, Grant T; Kundu, Madhuchhanda; Chandra, Sujyoti; Mondal, Susanta; Dasarathi, Sridevi; Mufson, Elliott J; Mishra, Rama K; Luan, Chi-Hao; Bennett, David A; Pahan, Kalipada.

In: The Journal of clinical investigation, 10.07.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selective disruption of TLR2/MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology

AU - Rangasamy, Suresh B

AU - Jana, Malabendu

AU - Roy, Avik

AU - Corbett, Grant T

AU - Kundu, Madhuchhanda

AU - Chandra, Sujyoti

AU - Mondal, Susanta

AU - Dasarathi, Sridevi

AU - Mufson, Elliott J

AU - Mishra, Rama K

AU - Luan, Chi-Hao

AU - Bennett, David A

AU - Pahan, Kalipada

PY - 2018/7/10

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N2 - Induction of TLR2 activation depends on its association with adapter protein MyD88. We have found that levels of TLR2 and MyD88 are elevated in the hippocampus and cortex of Alzheimer's disease (AD) patients and 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, but not other TLRs. Interestingly, wild type (wt) TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, double-stranded RNA, bacterial lipopolysaccharide, flagellin, and CpG DNA. After intranasal administration, wtTIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, wtTIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to 5XFAD mice, wtTIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of activated status of one component of the innate immune system by wtTIDM peptide may be beneficial in AD as well as other disorders in which TLR2-MyD88 signaling plays a role in disease pathogenesis.

AB - Induction of TLR2 activation depends on its association with adapter protein MyD88. We have found that levels of TLR2 and MyD88 are elevated in the hippocampus and cortex of Alzheimer's disease (AD) patients and 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, but not other TLRs. Interestingly, wild type (wt) TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, double-stranded RNA, bacterial lipopolysaccharide, flagellin, and CpG DNA. After intranasal administration, wtTIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, wtTIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to 5XFAD mice, wtTIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of activated status of one component of the innate immune system by wtTIDM peptide may be beneficial in AD as well as other disorders in which TLR2-MyD88 signaling plays a role in disease pathogenesis.

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DO - 10.1172/JCI96209

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JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

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