关于预防“阿尔茨海默氏症”药物的研发工作的一个主要焦点一直是，试图研发能减少神经毒性淀粉质-β肽在脑中积累的化合物。这种努力几乎没有成功的，部分是因为阻断γ-分泌酶的药物引起严重副作用，因为它们也阻断Notch（很多体内平衡功能所需的一种信号蛋白）的处理。现在，研究人员发现了一种“γ-分泌酶激发蛋白”(GSAP)，它选择性地控制淀粉质-β肽生成，而不会影响Notch解理。这个发现为抗“阿尔茨海默氏症”药物提出了一个可能的新目标。

抗癌药物imatinib (Gleevec)已知抑制淀粉质-β肽形成，而不会影响Notch解理，它被发现通过对GSAP的一个效应发挥作用。这表明，与imatinib 不同的是，能穿过“血脑屏障”的GSAP抑制因子也许有望能治疗“阿尔茨海默氏症”。

英文摘要：

Nature doi:10.1038/nature09325

Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease
Gen He,Wenjie Luo,Peng Li,Christine Remmers,William J. Netzer,Joseph Hendrick,Karima Bettayeb,Marc Flajolet,Fred Gorelick,Lawrence P. Wennogle& Paul Greengard

Accumulation of neurotoxic amyloid-β is a major hallmark of Alzheimer’s disease1. Formation of amyloid-β is catalysed by γ-secretase, a protease with numerous substrates2, 3. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective γ-secretase inhibitors that can reduce amyloid-β formation without impairing cleavage of other γ-secretase substrates, especially Notch, which is essential for normal biological functions3, 4. Here we report the discovery of a novel γ-secretase activating protein (GSAP) that drastically and selectively increases amyloid-β production through a mechanism involving its interactions with both γ-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-β production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-β concentrations. Knockdown of GSAP in a mouse model of Alzheimer’s disease reduces levels of amyloid-β and plaque development. GSAP represents a type of γ-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-β formation without affecting Notch cleavage5, achieves its amyloid-β-lowering effect by preventing GSAP interaction with the γ-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-β-lowering therapeutic target without affecting other key functions of γ-secretase.