Effects of transient cerebral ischemia on intracerebral amyloid beta metabolism and cognitive decline

• Project/Area Number: 17K11084
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Ehime University
• Principal Investigator: Min Li-Juan 愛媛大学, 医学系研究科, 講師 (80726175)
• Co-Investigator(Kenkyū-buntansha): 茂木 正樹 愛媛大学, 医学系研究科, 教授 (20363236) ; 堀内 正嗣 愛媛大学, 医学系研究科, 教授 (40150338) ; 岩波 純 愛媛大学, 医学系研究科, 准教授 (90624792)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 脳血管障害 / 脳虚血 / Aβタンパク / 認知障害 / 神経炎症 / 神経変性 / AT2受容体 / 脳血管保護作用 / Aβ脳室内投与 / 脳血管老化 / 炎症・酸化ストレス / 神経細胞障害 / Aβ投与 / 血管老化 / 認知機能 / 血管障害 / アミロイドアンギオパチー / アミロイドβの血管クリアランス機構 / レニン・アンジオテンシン系

Outline of Final Research Achievements

Our study examined the possibility that cerebral ischemia may increase Aβ-induced cognitive decline by increasing cerebrovascular senescence and Aβ clearance impairment, and the possible ameliorative role of angiotensin (Ang) II type 2 (AT2) receptor activation in this worsening of cognitive function. We demonstrated that cerebral ischemia potentially worsens Aβ-induced cognitive decline involving enhancement of oxidative stress and inflammation, impairment of RAGE-mediated Aβ clearance system, and exaggeration of cerebral Aβ level and neuronal degeneration. AT2 receptor activation in the cerebrovasculature could play a preventive role in this worsening of cognitive function through inhibition of oxidative stress, inflammation, impaired RAGE-mediated Aβ clearance system and neuronal degeneration.

Academic Significance and Societal Importance of the Research Achievements

本研究により、脳血管障害とADの病態を繋ぐメカニズムの一端が解明されるだけではなく、血管病の視点からも認知症の新しい予防・治療戦略に繋がるものと考える。例えば、Aβを標的とする効果的な開発には、脳血管機能の維持を考慮する必要があるというコンセプトの確立に貢献すると予想される。さらに、レニン-アンジオテンシン系(RAS)調節薬、例えば、Ang IIのAT1受容体阻害薬ARBやAT2受容体活性化剤C21は脳血管保護薬として、トランスレーショナル研究にあたり有効と考えられる。本研究結果は高齢者において、手術や麻酔後認知障害のメカニズムの解明にも結び付く可能性があり、大変有意義であると考えられる。

Research Products

• [Journal Article] Deterioration of cognitive function after transient cerebral ischemia with amyloid-beta infusion-possible amelioration of cognitive function by AT2 receptor activation (2020)
  • Author(s): Min LJ, Iwanami J, Shudou M, Bai HY, Shan BS, Higaki A, Mogi M, Horiuchi M
  • Journal Title: J Neuroinflammation Volume: 17 Issue: 1 Pages: 106-106
  • DOI: 10.1186/s12974-020-01775-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AT2 receptor stimulation inhibits phosphate-induced vascular calcification (2019)
  • Author(s): Kukida M, Mogi M, Kan-No H, Tsukuda K, Bai HY, Shan BS, Yamauchi T, Higaki A, Min LJ, Iwanami J, Okura T, Higaki J, Horiuchi M
  • Journal Title: Kidney Int. Volume: 95 Issue: 1 Pages: 138-148
  • DOI: 10.1016/j.kint.2018.07.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Attenuation of stroke damage by angiotensin II type 2 receptor stimulation via peroxisome proliferator-activated receptor-gamma activation (2018)
  • Author(s): Shan BS, Mogi M, Iwanami J, Bai HY, Kan-No H, Higaki A, Min LJ, Horiuchi M
  • Journal Title: Hypertens Res. Volume: 41 Issue: 10 Pages: 839-848
  • DOI: 10.1038/s41440-018-0082-9
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of interferon-regulatory factor-1 results in cognitive impairment (2018)
  • Author(s): Mogi M, Iwanami J, Wang XL, Tsukuda K, Kan-No H, Bai HY, Shan BS, Higaki A, Min LJ, Horiuchi M
  • Journal Title: Hypertens Res. Volume: 41 Issue: 10 Pages: 809-816
  • DOI: 10.1038/s41440-018-0080-y
  • Peer Reviewed / Open Access
• [Journal Article] Recognition of early stage thigmotaxis in Morris water maze test with convolutional neural network (2018)
  • Author(s): Higaki A, Mogi M, Iwanami J, Min LJ, Bai HY, Shan BS, Kan-No H, Ikeda S, Higaki J, Horiuchi M
  • Journal Title: PLoS One. Volume: 13 Issue: 5 Pages: e0197003-e0197003
  • DOI: 10.1371/journal.pone.0197003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Beneficial Effect of Mas Receptor Deficiency on Vascular Cognitive Impairment in the Presence of Angiotensin II Type 2 Receptor (2018)
  • Author(s): Higaki A, Mogi M, Iwanami J, Min LJ, Bai HY, Shan BS, Kukida M, Yamauchi T, Tsukuda K, Kan-No H, Ikeda S, Higaki J, Horiuchi M
  • Journal Title: J Am Heart Assoc. Volume: 7 Issue: 3
  • DOI: 10.1161/jaha.117.008121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predicting outcome of Morris water maze test in vascular dementia mouse model with deep learning (2018)
  • Author(s): Higaki A, Mogi M, Iwanami J, Min LJ, Bai HY, Shan BS, Kukida M, Kan-No H, Ikeda S, Higaki J, Horiuchi M
  • Journal Title: PLoS One Volume: 13 Issue: 2 Pages: e0191708-e0191708
  • DOI: 10.1371/journal.pone.0191708
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of angiotensin II type 2 receptor in mice with fetal growth restriction (2018)
  • Author(s): Yamauchi T, Mogi M, Kan-No H, Shan BS, Higaki A, Min LJ, Higaki T, Iwanami J, Ishii EI, Horiuchi M
  • Journal Title: Hypertens Res. Volume: 41 Issue: 3 Pages: 157-164
  • DOI: 10.1038/s41440-017-0004-2
  • Peer Reviewed / Open Access
• [Journal Article] Administration of bovine casein-derived peptide prevents cognitive decline in Alzheimer disease model mice. (2017)
  • Author(s): Min LJ, Kobayashi Y, Mogi M, Tsukuda K, Yamada A, Yamauchi K, Abe F, Iwanami J, Xiao JZ, Horiuchi M
  • Journal Title: PLoS One Volume: 12 Issue: 2 Pages: e0171515-e0171515
  • DOI: 10.1371/journal.pone.0171515
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] ヘスペリジンは血管障害モデルマウスにおける血管リモデリングを抑制する (2019)
  • Author(s): 成本葵、岩波純、成本悠、川上萌、山口りさこ、菅野晴美、茂木正樹、閔莉娟、堀内正嗣
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 胎児発育遅延による脳障害へのアンジオテンシンII2型受容体の保護効果 (2019)
  • Author(s): 成本悠、岩波純、単宝帥、茂木正樹、成本葵、閔莉娟、堀内正嗣
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Chronic Cerebral Damage Aggravates Vascular Remodeling in Cuff-Induced Vascular Injury Mouse Model (2019)
  • Author(s): Iwanami J, Mogi M, Tsukuda K, Higaki A, Kukida M, NakaokaH, Bai HY, Shan BS, Min LJ, Horiuchi M
  • Organizer: International Stroke Conference 2019
  • Int'l Joint Research
• [Presentation] Angiotensin II and Amyloid-β Synergistically Induce Brain Vascular Smooth Muscle Cell Senescence (2018)
  • Author(s): Min LJ, Bai HY, Shan BS, Kan-no H, Higaki A, Iwanami J, Mogi M, Horiuchi M
  • Organizer: The 27th Scientific Meeting of the International Society of Hypertension, 2018
  • Int'l Joint Research
• [Presentation] Interaction between Ischemic Brain Damage and Amyloid-beta Infusion in Cognitive Impairment ~Possible Amelioration of Cognitive Function by AT2 Receptor Activation~ (2018)
  • Author(s): Min LJ, Mogi M, Bai HY, Shan BS, Higaki A, Iwanami J, Horiuchi M
  • Organizer: The 27th Scientific Meeting of the International Society of Hypertension, 2018
  • Int'l Joint Research
• [Presentation] Synergistic Effect of Angiotensin II and Amyloid-β on Brain Vascular Smooth Muscle Cell Senescence (2018)
  • Author(s): Min LJ, Bai HY, Shan BS, Kan-no H, Higaki A, Mogi M, Iwanami J, Horiuchi M
  • Organizer: AHA Council on Hypertension 2018
  • Int'l Joint Research
• [Presentation] Cerebral Ischemia with Amyloid-beta Infusion Deteriorates Cognitive Decline ~Possible Amelioration of Cognitive Function by AT2 Receptor Activation~ (2018)
  • Author(s): Min LJ, Mogi M, Bai HY, Shan BS, Higaki A, Iwanami J, Horiuchi M
  • Organizer: AHA Council on Hypertension 2018
  • Int'l Joint Research
• [Presentation] Hesperidin in citrus fruit juice plays a role in preventing cognitive impairment induced by ischemic brain damage (2018)
  • Author(s): Kawakami M, Iwanami J, Tsukuda K, Higaki A, Min LJ, Mogi M, Horiuchi M
  • Organizer: AHA Council on Hypertension 2018
  • Int'l Joint Research
• [Presentation] Chronic cerebral ischemic injury worsens vascular dysfunction (2018)
  • Author(s): Iwanami J, Mogi M, Tsukuda K, Higaki A, Kawakami M, Kukida M, NakaokaH, Yamauchi T, Bai HY, Shan BS, Min LJ, Horiuchi M
  • Organizer: AHA Council on Hypertension 2018
  • Int'l Joint Research
• [Presentation] Amelioration of Ischemic Brain Injury by Angiotensin II Type 2 Receptor Stimulation via Peroxisome Proliferator-Activated Receptor-gamma Activation (2018)
  • Author(s): Shan BS, Mogi M, Iwanami J, Kan-no H, Bai HY, Higaki A, Min LJ, Horiuchi M
  • Organizer: The 27th Scientific Meeting of the International Society of Hypertension, 2018
  • Int'l Joint Research
• [Presentation] Role of the angiotensin receptor subtypes in the brain (2018)
  • Author(s): Horiuchi M
  • Organizer: The 27th Scientific Meeting of the International Society of Hypertension, 2018
  • Int'l Joint Research / Invited
• [Presentation] T2 receptor stimulation-induced protective effect on ischemic brain damage is enhanced by AT2 receptor-interacting protein (2018)
  • Author(s): Mogi M, Iwanami J, Bai HY, Shan BS, Min LJ, Liu S, Horiuchi M
  • Organizer: The 27th Scientific Meeting of the International Society of Hypertension, 2018
  • Int'l Joint Research
• [Presentation] 生活習慣病予防よりみた認知症改善へのアプローチ (2018)
  • Author(s): 岩波純、堀内正嗣
  • Organizer: 脳心血管抗加齢研究会2018（併催）アンチエイジングフェスタ2018
  • Invited
• [Presentation] Interaction between Stroke and Amyloid-beta Deposition in Cognitive Function~Possible Involvement of Antagonist Effect of AT2 Receptor Activation~ (2017)
  • Author(s): Li-Juan Min, Masaki Mogi, Kana Tsukuda, Akinori Higaki, Masanori Kukida, Toshifumi Yamauchi, Xiao-Li Wang, Hui-Yu Bai, Bao-Shuai Shan, Jun Iwanami and Masatsugu Horiuchi
  • Organizer: International Stroke Conference 2017
  • Int'l Joint Research
• [Presentation] Interaction between Ischemic Brain Injury and Amyloid-beta Deposition in Cognitive Decline; Possible Cognitive Protection by AT2 Receptor Activation (2017)
  • Author(s): Li-Juan Min, Masaki Mogi, Kana Tsukuda, Hui-Yu Bai, Bao-Shuai Shan, Akinori Higaki, Jun Iwanami and Masatsugu Horiuchi
  • Organizer: AHA Council on Hypertension 2017
  • Int'l Joint Research
• [Presentation] 虚血性脳障害とアミロイドβの認知機能における相互作用~AT2受容体による相互作用抑制効果の可能性~ (2017)
  • Author(s): 閔 莉娟、茂木正樹、佃 架奈、白 薈鈺、単 宝帥、檜垣彰典、岩波 純、堀内正嗣
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] 認知機能における虚血性脳障害とアミロイドβの相互作用～AT2受容体による相互作用抑制効果の可能性～ (2017)
  • Author(s): 閔 莉娟、茂木正樹、檜垣彰典、岩波 純、堀内正嗣
  • Organizer: 脳心血管抗加齢研究会 2017
• [Presentation] Cross-talk between amyloid-beta and angiotensin II in brain vascular smooth muscle cell senescence (2017)
  • Author(s): Hui-Yu Bai, Li-Juan Min, Bao-shuai Shan, Harumi Kan-no, Akinori Higaki, Jun Iwanami, Masaki Mogi and Masatsugu Horiuchi
  • Organizer: 第40回日本高血圧学会総会