Drug discovery research for Alzheimer's disease targeting a novel SV2B-BACE1 interaction

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07884
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kyoto University
• Principal Investigator: Kuzuya Akira 京都大学, 医学研究科, 准教授 (30422950)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: シナプス小胞蛋白2B / BACE1 / シナプス / アミロイドβ蛋白

Outline of Final Research Achievements

In this study, we examined whether SV2B, a novel synaptic protein that binds to BACE1, the protease responsible for the production of the pathogenic protein Aβ, is involved in sporadic Alzheimer's disease (AD) pathology using samples from AD patients. The results revealed a significant early reduction of SV2B in AD postmortem brains compared to other synaptic proteins. SV2B fragments were also detected in the cerebrospinal fluid, indicating the potential of SV2B as a candidate biomarker for AD (currently undergoing patent application). Using in vivo microdialysis in mouse brains, we established a measurement system for endogenous levels of Aβ and sAPPβ in the hippocampal interstitial fluids and conducted preliminary experiments for the introduction of human SV2B gene into the hippocampus using SV2B knockout mice, which are currently being maintained.

Free Research Field

アルツハイマー病の分子生物学

Academic Significance and Societal Importance of the Research Achievements

今回申請者が着目するSV2Bは、主に興奮性シナプスに発現するシナプス小胞蛋白であり、BACE1とともにADの初期病変部である海馬の興奮性プレシナプスに豊富に局在し、BACE1のAPP切断活性の抑制に関わる可能性がある。SV2Bを標的分子とすることにより、興奮性シナプスにおけるBACE1のAPP切断活性の指標となる新規バイオマーカーの創出や抗シナプスAβ療法の開発につながることが期待される。