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タイトル: | Pericyte-derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion |
著者: | Uemura, Maiko T. Ihara, Masafumi Maki, Takakuni Nakagomi, Takayuki Kaji, Seiji Uemura, Kengo Matsuyama, Tomohiro Kalaria, Raj N. Kinoshita, Ayae Takahashi, Ryosuke https://orcid.org/0000-0002-1407-9640 (unconfirmed) |
著者名の別形: | 上村, 麻衣子 眞木, 崇州 梶, 誠兒 |
発行日: | Jul-2018 |
出版者: | Wiley-Blackwell |
誌名: | Brain Pathology |
巻: | 28 |
号: | 4 |
開始ページ: | 521 |
終了ページ: | 535 |
抄録: | Subcortical small vessel disease (SVD) is characterized by white matter damage resulting from arteriolosclerosis and chronic hypoperfusion. Transforming growth factor beta 1 (TGFB1) is dysregulated in the hereditary SVD, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). However, very little is known about the role of the largest group in the TGFB superfamily – the bone morphogenetic proteins (BMPs) – in SVD pathogenesis. The aim of this study was to characterize signaling abnormalities of BMPs in sporadic SVD. We examined immunostaining of TGFB1 and BMPs (BMP2/BMP4/BMP6/BMP7/BMP9) in a total of 19 post-mortem human brain samples as follows: 7 SVD patients (4 males, 76–90 years old); 6 Alzheimer's disease (AD) patients (2 males, 67–93 years old) and 6 age-matched disease controls (3 males, 68–78 years old). We subsequently investigated the effects of oxygen–glucose deprivation and BMP4 addition on cultured cells. Furthermore, adult mice were subjected to chronic cerebral hypoperfusion using bilateral common carotid artery stenosis, followed by continuous intracerebroventricular infusion of the BMP antagonist, noggin. In the SVD cases, BMP4 was highly expressed in white matter pericytes. Oxygen–glucose deprivation induced BMP4 expression in cultured pericytes in vitro. Recombinant BMP4 increased the number of cultured endothelial cells and pericytes and converted oligodendrocyte precursor cells into astrocytes. Chronic cerebral hypoperfusion in vivo also upregulated BMP4 with concomitant white matter astrogliogenesis and reduced oligodendrocyte lineage cells, both of which were suppressed by intracerebroventricular noggin infusion. Our findings suggest ischemic white matter damage evolves in parallel with BMP4 upregulation in pericytes. BMP4 promotes angiogenesis, but induces astrogliogenesis at the expense of oligodendrocyte precursor cell proliferation and maturation, thereby aggravating white matter damage. This may explain white matter vulnerability to chronic hypoperfusion. The regulation of BMP4 signaling is a potential therapeutic strategy for treating SVD. |
記述: | 孤発性小血管性認知症の発症機序の一部を解明 --認知症の治療に向けての新たなアプローチ、マウスで効果を確認-- 京都大学プレスリリース. 2017-06-01. |
著作権等: | © 2017 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
URI: | http://hdl.handle.net/2433/225117 |
DOI(出版社版): | 10.1111/bpa.12523 |
PubMed ID: | 28470822 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2017-06-01 |
出現コレクション: | 学術雑誌掲載論文等 |
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