Examining the risk of developing Alzheimer's disease induced by decreased expression of ILEI

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16491
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: WATANABE Naoki 滋賀医科大学, 神経難病研究センター, 助教 (60769339)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: アルツハイマー病 / Amyloid-β / ILEI / 遺伝子発現制御 / 老年期認知症

Outline of Final Research Achievements

Reporter assay revealed two transcriptionally active regions of ILEI gene near the transcription start site, and transcription factors SP1 and EBF1 were found by database search, knockdown, and forced expression. RNA-seq revealed decreased ILEI in AD brain and decreased binding of SP1 and EBF1 to this region in AD brain.
App(NL-F);ILEI-cKO mice, which can be induced with a neural-specific defect, were generated and crossed with the App(NL-F) strain, and after defect induction at 3 and 6 months of age, increased Aβ deposition was observed in the brains of App(NL-F);ILEI-cKO mice compared to the control mice at 14 months of age by immunohistochemical staining and ELISA. Y-maze test showed that the working memory of App(NL-F);ILEI-cKO mice was impaired compared to the control mice after 10 months of age.

Free Research Field

分子神経科学

Academic Significance and Societal Importance of the Research Achievements

ILEIはγセクレターゼ活性を阻害せず、Aβの基質APP-C99の不安定化によりAβ産生を減少させる。このためγセクレターゼによる治療法開発で従来問題になったNotch阻害による副作用を回避した治療標的として有望であり、脳内Aβ蓄積のリスク評価を標的としたバイオマーカーとしても期待できる。ILEIの特異な活性や脳内発現について申請者らが初めて見出したもので、本研究は独自性が高く、今後さらに新たな研究領域を生む創造性も期待できる。将来、高齢者スクリーニングとしてILEIを含めたバイオマーカーを評価し、リスクを推定した上で、予防的治療を加えるという認知症の先制医療の実現を目指し、研究を進めている。