Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer’s pathology
Suresh B. Rangasamy, … , David A. Bennett, Kalipada Pahan
Suresh B. Rangasamy, … , David A. Bennett, Kalipada Pahan
Published July 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4297-4312. https://doi.org/10.1172/JCI96209.
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Research Article Inflammation Neuroscience

Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer’s pathology

Abstract

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

Authors

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

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Figure 2

Design of a peptide for disruption of TLR2 and MyD88 interaction.

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Design of a peptide for disruption of TLR2 and MyD88 interaction. (A) A ...
(A) A rigid-body, in silico docked pose of mouse TLR2 (blue) and MyD88 (green) (electrostatic energy = –7.750 kcal/mol; desolvation energy = –24.99 kcal/mol; VDW energy = 105.25 kcal/mol; total energy = –22.216 kcal/mol) shows strong interaction between amino acids 245 and 250 of the CD loop of MyD88 and the BB loop of TLR2. Therefore, the peptide corresponding to this domain of MyD88 (TIDM) was used to dissociate the interaction between TLR2 and MyD88. (B) TLR2-MyD88 interaction was complexed with the WT TIDM peptide (electrostatic energy = –4.516 kcal/mol; desolvation energy = –24.027 kcal/mol; VDW energy = 16.724 kcal/mol; total energy = –26.871 kcal/mol). (C) Generation of a cMyc-tagged cTLR2 recombinant protein. Amp, ampicillin resistance. The in vitro binding affinity of increasing doses of WT TIDM (D) and mTIDM (E) with cTLR2 was examined using SPR analyses (n = 2 replicates/dose in 3 independent experiments). (F) Plot of the binding response values versus the concentrations of WT TIDM (circles) and mTIDM (squares) peptides. (G) Melting curve of cTLR2 protein (black) alone and with WT TIDM peptides (green). Thermal shift analyses showed a 4.96°C shift of the melting temperature (ΔTm) (n = 2 replicates/dose in 3 independent experiments). (H) Melting curve of cTLR2 protein (black) alone and with mTIDM peptides (red) indicated a ΔTm of 0.87°C (n = 2 replicates/dose in 3 independent experiments). μRIU, micro refractive index units. Data represent the mean ± SEM.