Functional changes in LRP1 in neurons after cerebral infarction and therapeutic strategies

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08289
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Takagi Norio 東京薬科大学, 薬学部, 教授 (50318193)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 脳虚血

Outline of Final Research Achievements

The present study suggested that LRP1 in neurons was cleaved after cerebral infarction and might lead to brain dysfunction. In addition, it was revealed that this LRP1 cleavage caused a marked increase in the intracellular domain and a decrease in the extracellular domain, and the intracellular domain of LRP1 was localized in the perinuclear region after NMDA treatment. In addition to clarifying the role of furin involved in this cleavage, we also elucidated that furin inhibitor dose-dependently prevented neuronal injury induced by NMDA treatment. These useful findings would contribute to the development of therapeutic agents for cerebral infarction.

Free Research Field

神経生化学・薬理学

Academic Significance and Societal Importance of the Research Achievements

脳神経では、NMDA受容体を介する神経障害に対して LRP1 は保護効果を発揮せず、その原因として虚血性障害で誘導される LRP1 の切断による機能不全が考えられた。この切断に関わる furin の役割を示すとともに、furin阻害薬の脳神経保護効果を明らかにした。NMDA 受容体を介する神経障害は様々な中枢神経疾患の病態形成に寄与していることから、LRP1 の機能不全の機序解明は治療困難な中枢神経系疾患に対する治療法開発に有益な波及効果をもたらすものと考えられる。