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Transthyretin variants impact blood-nerve barrier and neuroinflammation in amyloidotic neuropathy
http://hdl.handle.net/2237/0002013546
http://hdl.handle.net/2237/0002013546a446fabb-98ca-4776-b7ba-b7d90b37a459
| 名前 / ファイル | ライセンス | アクション |
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ATTRv_inflam_manuscript.pdf (518 KB)
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Figure1.pdf (741 KB)
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Figure2.pdf (243 KB)
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Figure3.pdf (322 KB)
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Figure4.pdf (178 KB)
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Figure5.pdf (162 KB)
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Figure6.pdf (216 KB)
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Figure7.pdf (308 KB)
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Supplementary_Materials_clean_20241123.pdf (483 KB)
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Supplementary_Figure1.pdf (137 KB)
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Supplementary_Figure2.pdf (168 KB)
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| アイテムタイプ | itemtype_ver1(1) | |||||||||||||||||||||||||||||||||||||||
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| 公開日 | 2025-10-14 | |||||||||||||||||||||||||||||||||||||||
| タイトル | ||||||||||||||||||||||||||||||||||||||||
| タイトル | Transthyretin variants impact blood-nerve barrier and neuroinflammation in amyloidotic neuropathy | |||||||||||||||||||||||||||||||||||||||
| 言語 | en | |||||||||||||||||||||||||||||||||||||||
| 著者 |
Chao, Chi-Chao
× Chao, Chi-Chao
× Yang, Wei-Kang
× Yeh, Ti-Yen
× Kan, Yu-Yu
× Wang, Yi-Shiang
× Lee, Kuan-Jung
× Hu, Chieh-Ju
× Tang, Tsz-Yi
× Ide, Toshihiro
× Hsueh, Hsueh-Wen
× Lin, Cheng-Chen
× Shy, Horng-Tzer
× Lee, Ming-Jen
× Tzeng, Shiou-Ru
× Katsuno, Masahisa
× Koike, Haruki
× Hsieh, Sung-Tsang
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| アクセス権 | ||||||||||||||||||||||||||||||||||||||||
| アクセス権 | embargoed access | |||||||||||||||||||||||||||||||||||||||
| アクセス権URI | http://purl.org/coar/access_right/c_f1cf | |||||||||||||||||||||||||||||||||||||||
| 権利 | ||||||||||||||||||||||||||||||||||||||||
| 権利情報 | This is a pre-copyedited, author-produced version of an article accepted for publication in [BRAIN] following peer review. The version of record [Chi-Chao Chao, Wei-Kang Yang, Ti-Yen Yeh, Yu-Yu Kan, Yi-Shiang Wang, Kuan-Jung Lee, Chieh-Ju Hu, Tsz-Yi Tang, Toshihiro Ide, Hsueh-Wen Hsueh, Cheng-Chen Lin, Horng-Tzer Shy, Ming-Jen Lee, Shiou-Ru Tzeng, Masahisa Katsuno, Haruki Koike, Sung-Tsang Hsieh, Transthyretin variants impact blood–nerve barrier and neuroinflammation in amyloidotic neuropathy, Brain, Volume 148, Issue 7, July 2025, Pages 2537–2550, https://doi.org/10.1093/brain/awaf028] is available online at: https://doi.org/10.1093/brain/awaf028. | |||||||||||||||||||||||||||||||||||||||
| 言語 | en | |||||||||||||||||||||||||||||||||||||||
| 内容記述 | ||||||||||||||||||||||||||||||||||||||||
| 内容記述タイプ | Abstract | |||||||||||||||||||||||||||||||||||||||
| 内容記述 | Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a neurodegenerative disease caused by mutations in the gene encoding transthyretin (TTR). Although amyloid deposition is pathognomonic for diagnosis, this pathology in nervous tissues cannot fully account for nerve degeneration, implying additional pathophysiology for neurodegeneration, which, however, has not yet been elucidated fully. In this study, neuroinflammation in ATTRv-PN was investigated by examining nerve morphometry, the blood–nerve barrier and macrophage infiltration in the sural nerves of ATTRv-PN patients and the sciatic nerves of a complementary mouse system, i.e. the humanized knock-in hTTRA97S mouse. The direct effects of mutant TTR proteins were evaluated in these hTTRA97S mice in vivo and in a human umbilical vein endothelial cell (HUVEC) model in vitro. This case–control and cross-sectional study included 19 patients [17 men; 62.9 ± 3.9 years of age; familial amyloid polyneuropathy (FAP) stage 1, n = 11; FAP stage 2, n = 7; FAP stage 3, n = 1] with p.Ala117Ser (A97S) and 46 patients (39 men; 65.3 ± 11.4 years of age; FAP stage 1, n = 31; FAP stage 2, n = 12; FAP stage 3, n = 3) with p.Val50Met (V30M). Both genotypes had elevated protein in the CSF: 88.9% (16 cases in 18 patients) in A97S and 51.1% (23 cases in 45 patients) in V30M. The myelinated nerve fibres in sural nerves were markedly depleted in ATTRv-PN, and the myelinated nerve fibre density was inversely correlated with CSF protein, implying leakage of the blood–nerve barrier. The tight junction ultrastructure of the endoneurial microvessels in sural nerves was impaired, as indicated by the reduced expression of zonula occludens-1 (ZO-1). The cultured HUVECs that were not transfected with any TTR gene variant presented reduced ZO-1 expression when exposed to mutant recombinant TTR of A97S or V30M compared with wild-type TTR. Increased infiltration of macrophages with expression of the inflammasome maker, NLR family pyrin domain containing 3 (NLRP3), suggested that polarization to the pro-inflammatory M1 lineage was robust in the sural nerves of ATTRv-PN patients and the sciatic nerves of hTTRA97S mice compared with those of controls and wild-type mice. In parallel, the mRNA expression of interleukin-1β was greater in the sural nerves of ATTRv-PN than in those of the controls. In conclusion, the disrupted blood–nerve barrier attributable to mutant TTR protein resulting in an increased CSF protein level was associated with nerve degeneration in ATTRv-PN via the infiltration of inflammatory macrophages and the production of inflammatory cytokines. | |||||||||||||||||||||||||||||||||||||||
| 言語 | en | |||||||||||||||||||||||||||||||||||||||
| 出版者 | ||||||||||||||||||||||||||||||||||||||||
| 出版者 | Oxford University Press | |||||||||||||||||||||||||||||||||||||||
| 言語 | en | |||||||||||||||||||||||||||||||||||||||
| 言語 | ||||||||||||||||||||||||||||||||||||||||
| 言語 | eng | |||||||||||||||||||||||||||||||||||||||
| 資源タイプ | ||||||||||||||||||||||||||||||||||||||||
| 資源タイプresource | http://purl.org/coar/resource_type/c_6501 | |||||||||||||||||||||||||||||||||||||||
| タイプ | journal article | |||||||||||||||||||||||||||||||||||||||
| 出版タイプ | ||||||||||||||||||||||||||||||||||||||||
| 出版タイプ | AM | |||||||||||||||||||||||||||||||||||||||
| 出版タイプResource | http://purl.org/coar/version/c_ab4af688f83e57aa | |||||||||||||||||||||||||||||||||||||||
| 関連情報 | ||||||||||||||||||||||||||||||||||||||||
| 関連タイプ | isVersionOf | |||||||||||||||||||||||||||||||||||||||
| 識別子タイプ | DOI | |||||||||||||||||||||||||||||||||||||||
| 関連識別子 | https://doi.org/10.1093/brain/awaf028 | |||||||||||||||||||||||||||||||||||||||
| 収録物識別子 | ||||||||||||||||||||||||||||||||||||||||
| 収録物識別子タイプ | PISSN | |||||||||||||||||||||||||||||||||||||||
| 収録物識別子 | 0006-8950 | |||||||||||||||||||||||||||||||||||||||
| 書誌情報 |
en : BRAIN 巻 148, 号 7, p. 2537-2550, 発行日 2025-07 |
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| ファイル公開日 | ||||||||||||||||||||||||||||||||||||||||
| 日付 | 2026-07-01 | |||||||||||||||||||||||||||||||||||||||
| 日付タイプ | Available | |||||||||||||||||||||||||||||||||||||||
