＜シンポジウム（2）―11―2＞アルツハイマー病の新展開―分子病態から治療戦略へ
γセクレターゼ活性制御機構の理解に基づいたアルツハイマー病治療薬開発
富田 泰輔
東京大学大学院薬学系研究科臨床薬学教室〔〒116―0003 東京都文京区本郷7―3―1〕
Genetic and biological studies provide strong evidence that the deposition of amyloid-β peptide (Aβ) contributes to the etiology of Alzheimer's disease (AD). Thus, drugs that regulate the brain Aβ levels could provide effective disease-modifying therapy for AD. Aβ is generated from amyloid-β precursor protein (APP) by β- and γ-secretases. Several γ-secretase inhibitors have been developed as AD therapeutics. However, simple inhibition of γ-secretase would have adverse consequences, as γ-secretase is involved in several signaling pathways including Notch signaling. In 2010, the development of semagacestat, a γ-secretase inhibitor, was halted. Preliminary results from Phase III studies showed that semagacestat failed to slow disease progression, and it was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Furthermore, semagacestat treatment was associated with an increased risk of skin cancer. Thus, alternative compounds that indirectly modulate γ-secretase activity without affecting Notch are attracting attention. However, molecular mechanism of these compounds still remains unclear. To develop therapeutics with superior specificity and high potency for AD, we have been analyzing the mode of actions of known compounds, structure-and-function relationship of the γ-secretase complex and possible rational design of γ-secretase inhibitors and modulators using chemical biology.
Full Text of this Article in Japanese PDF (244K)
(臨床神経, 52：1165−1167, 2012)
key words：アミロイド，アルツハイマー，セクレターゼ，リスク因子
（受付日：2012年5月24日）
