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 5

After intranasal delivery, WT TIDM peptide enters into the hippocampus and suppresses glial activation and reduces plaques in the hippocampus of Tg mice.

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After intranasal delivery, WT TIDM peptide enters into the hippocampus a...
Tg mice (6 months of age) received 1 intranasal dose of WT TIDM peptide (0.1 mg/kg BW). After 60 minutes of treatment, mice were perfused with sterile saline, and hippocampi were homogenized and supernatant analyzed for WT TIDM by ESI-MS (A, WT TIDM standard; B, untreated 5XFAD-Tg; C, WT TIDM–treated 5XFAD-Tg). Tg mice were treated with WT TIDM and mTIDM peptides (0.1 mg/kg body WT/2d) via the intranasal route. After 30 days, hippocampal sections were double labeled for Iba-1 and p-p65 (D) and Iba-1 and iNOS (Supplemental Figure 9). Cells positive for Iba-1 (E, CA1; F, CA3), p-p65 (G, CA1; H, CA3), and iNOS (I, CA1; J, CA3) were counted in 2 sections (2 images/slide) from each of 6 different mice (n = 6) per group. †P < 0.001 versus non-Tg; ††P < 0.001 versus Tg; 2-sample t test. (K) Hippocampal extracts from all groups of mice (n = 4 per group) were immunoblotted for iNOS. Actin was run as a loading control. Bands were scanned, and values (L, iNOS/actin) are presented relative to the non-Tg control. †P < 0.001 versus non-Tg; ††P < 0.001 versus Tg; 2-sample t test. (M) Hippocampal sections were immunolabeled with 82E1 mAb. Amyloid plaques (N, cortex; O, hippocampus) were counted in 2 sections (2 images/slide) from each of 6 different mice per group. †P < 0.001 versus non-Tg; ††P < 0.001 versus Tg; 2-sample t test. (P) Hippocampal extracts (n = 4 per group) were analyzed for Aβ by Western blotting using 6E10 mAb. Arrowhead indicates a 4-kDa Aβ band. MW, molecular weight. (Q) Bands were scanned, and values (Aβ/actin) are presented relative to the non-Tg control. †P < 0.001 versus non-Tg; ††P < 0.001 versus Tg; 2-sample t test. ve, vehicle. Scale bars: 100 μm. Data represent the mean ± SEM.