High dimensional analysis of neurovasculature to reveal molecular mechanism of aged or neurodegenerative brain

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07831
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Institute of Physical and Chemical Research (2021-2022); Juntendo University (2019-2020)
• Principal Investigator: Fukuhara Takeshi 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (20359673)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: パーキンソン病 / 炎症 / 免疫 / アストロサイト / 老化

Outline of Final Research Achievements

This study aimed to unravel the underlying mechanism of Parkinson’s disease, especially at the viewpoint from neurovascular-immune interaction. To do this, various inflammatory markers of vasculature or myeloid cells were tested in aged mice cohort as well as PARK2-deficient cohort. Due to the progressive phenotype of PARK2 mutation in patient, the responsible mice mutant was employed in this study for further analysis. Besides immunohistochemical analysis, RNA-seq analysis of brain was performed against 16 or 28 months old cohort. Although there are no prominent genes expressed between wildtype or PARK2 mutant, aging itself forced to increase a few marker including C4b that are one of complement factors. In PARK2 mutant background, we observed age from 16 to 28 monts with increased expression of GFAP (astrocyte marker) and Lyz2 (myeloid marker). These dataset suggest that a subtle change in glia promoted age-related chronic inflammation.

Free Research Field

神経免疫学

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病は根治療法のない神経変性疾患であり、家族性および孤発性のいずれにおいても対処療法しか治療法がない。このため、疾患修飾療法としての先制医療が期待されている。近年では脳内炎症に限らず、腸管をはじめとした末梢臓器の炎症がパーキンソン病の進行に寄与していると考えられる報告があり、注目を集めている。本研究は、脳と末梢臓器をつなぐ脳血管に着目し、炎症血管マーカーなどを検索した。老化に対する治療法やパーキンソン病の治療作用点として妥当性の検証が必要となるが、老化に連動して発現上昇するC4bやLyz2を分子標的とした創薬探索が今後期待される。