Wolfe Michael S
Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
BMC Neurosci. 2008 Dec 3;9 Suppl 2(Suppl 2):S4. doi: 10.1186/1471-2202-9-S2-S4.
The amyloid-beta peptide (Abeta), implicated in the pathogenesis of Alzheimer's disease (AD), is produced through sequential proteolysis of the Abeta precursor protein (APP) by beta- and gamma-secretases. Thus, blocking either of these two proteases, directly or indirectly, is potentially worthwhile toward developing AD therapeutics. beta-Secretase is a membrane-tethered pepsin-like aspartyl protease suitable for structure-based design, whereas gamma-secretase is an unusual, heterotetrameric membrane-embedded aspartyl protease. While gamma-secretase inhibitors entered clinical trials first due to their superior pharmacological properties (for example, brain penetration) over beta-secretase inhibitors, it has since become clear that gamma-secretase inhibitors can cause mechanism-based toxicities owing to interference with the proteolysis of another gamma-secretase substrate, the Notch receptor. Strategies for targeting Abeta production at the gamma-secretase level without blocking Notch signalling will be discussed. Other strategies utilizing cell-based screening have led to the identification of novel Abeta lowering agents that likewise leave Notch proteolysis intact. The mechanism by which these agents lower Abeta is unknown, but these compounds may ultimately reveal new targets for AD therapeutics.
β-淀粉样肽（Aβ）与阿尔茨海默病（AD）的发病机制有关，它是由β-分泌酶和γ-分泌酶对Aβ前体蛋白（APP）进行顺序蛋白水解而产生的。因此，直接或间接阻断这两种蛋白酶中的任何一种，对于开发AD治疗药物可能都是值得的。β-分泌酶是一种与膜结合的胃蛋白酶样天冬氨酸蛋白酶，适合基于结构的设计，而γ-分泌酶是一种不同寻常的、异源四聚体膜嵌入天冬氨酸蛋白酶。虽然γ-分泌酶抑制剂由于其比β-分泌酶抑制剂具有更优越的药理特性（例如，脑渗透性）而首先进入临床试验，但后来已经清楚，γ-分泌酶抑制剂由于干扰另一种γ-分泌酶底物Notch受体的蛋白水解而可导致基于机制的毒性。将讨论在不阻断Notch信号传导的情况下在γ-分泌酶水平靶向Aβ产生的策略。利用基于细胞的筛选的其他策略已导致鉴定出同样使Notch蛋白水解保持完整的新型Aβ降低剂。这些药物降低Aβ的机制尚不清楚，但这些化合物最终可能会揭示AD治疗的新靶点。
