Investigation of the mechanism worsening Alzheimer's disease by vascular endothelial dysfunction in cerebral amyloid angiopathy.

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16022
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Foundation for Biomedical Research and Innovation at Kobe
• Principal Investigator: Sasahara Tomoya 公益財団法人神戸医療産業都市推進機構, その他部局等, 研究員(上席・主任研究員クラス) (30735345)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 血管内皮 / 血管機能障害 / アミロイドβ / アミロスフェロイド / β-セクレターゼ / δ-セクレターゼ / 脳血管アミロイド血症 / アルツハイマー病

Outline of Final Research Achievements

Cerebral amyloid angiopathy worsens Alzheimer's disease. However, the detailed molecular mechanism remains unclear. In this study, to elucidate the molecular mechanism, we first constructed a novel culture system of cerebral neuro-vascular unit using cerebrovascular endothelial cells, brain pericytes, and cerebral cortex-derived primary culture. We then found that treatment of vascular cells in this culture system with amylospheroid (a neurotoxic and vasotoxic amyloid-β aggregate deposited in cerebral blood vessels in Alzheimer’s patients) increases BACE protein level via angiotensin II release from endothelial cells and subsequent neuronal AT2 receptor-B2 receptor-BACE mRNA transcription pathway. We additionally found that amylospheroid acts on pericytes and then neuronal AEP is activated. Because both BACE and AEP increase amyloid-β release, the molecular mechanism found in this study may be a useful therapeutic target for Alzheimer’s disease.

Free Research Field

循環器薬理学

Academic Significance and Societal Importance of the Research Achievements

本研究ではAβ遊離を促進する2つの酵素βセクレターゼ（BACE）とδセクレターゼ(AEP)が血管障害により増悪することを解明した。脳実質でのアミロイドβ沈着はアルツハイマー病発症の十数年前から起きているが、血管障害があるとAβ沈着量が増加することが知られており、今回の研究成果はこの現象の分子機序の解明とそれに基づく新規アルツハイマー病治療薬の開発につながると期待される。