Can the age-related decrease in the expression of the novel secretory molecule ILEI be the primary factor in Alzheimer's disease?

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K17812
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurophysiology / General neuroscience; Nerve anatomy/Neuropathology
• 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): 2017-04-01 – 2020-03-31
• Keywords: アルツハイマー病 / 遺伝子発現制御 / 脳神経疾患 / 老化 / 神経科学 / ILEI / Amyloid-β / γ-Secretase

Outline of Final Research Achievements

The purpose of this study was to analyze the primary causes of Aβ accumulation in the brain, which is the basic pathophysiology of AD, and to contribute to the development of pre-emptive treatment and diagnosis.
To elucidate the mechanism of down-regulation of ILEI expression, we identified the promoter region of ILEI gene and endogenous transcription factors, suggesting that the down-regulation of ILEI expression in the AD brain is due to the down-regulation of the transcription factors.
To test whether the decreased expression level of ILEI in the brain is a risk factor for the development of AD, we generated ILEI KO and cKO mice by genome editing, and confirmed the disappearance and decrease of ILEI expression in these mice, respectively. These mice were crossed with App(NL-F) and App(NL-G-F) mice, and the analyses are in progress.

Free Research Field

分子神経科学

Academic Significance and Societal Importance of the Research Achievements

これまで認知症の複数の臨床治験が進められたが、多くは効果不足と副作用から中断を余儀なくされてきた。認知症発症に25年以上先行するとされるAβ蓄積の初期ないし蓄積前からのAβ抑制を行う先制医療の実現のためには、脳内Aβ蓄積の一次的要因を明らかにすることが重要な課題となる。しかし、これまでその知見は極めて乏しく、これが先制医療実現の障壁になっている。本研究による脳内ILEI発現低下機構及びAD発症のリスク因子の検証の成果は、発症前診断法や先制治療法の開発につながるものである。