Inhibition of Alzheimer's Beta-Amyloid Fibril Formation

阿尔茨海默病（AD）是一种进行性和不可逆的脑部疾病，目前尚无治愈方法。一个小 淀粉样β肽（Abeta）是一种含有39-43个氨基酸的蛋白质，被广泛认为是导致 疾病最近的证据表明，Abeta的可溶性低聚物可能是主要的毒性物质 AD患者的淀粉样蛋白公认的是，新产生的Abeta是单体的、可溶的和无毒的，采用 无规卷曲/α-螺旋混合物结构。在AD中，Abeta经历 从无规卷曲/α-螺旋到β-折叠结构的构象变化，导致寡聚化， 降水在寻找阻止这种构象变化的化合物时，我们发现， 三环吡喃酮（TP），特别是CP 2（代号），阻止人神经母细胞瘤MC 65细胞的死亡 与含A β代谢物的细胞内积累有关。CP 2抑制Abeta 1- A β 1 -40和A β 1 -42肽，阻断A β 1 -40和A β 1 -42 β折叠形成，并结合A β 体外肽。CP 2也能穿透小鼠血脑屏障。这些令人兴奋的结果表明，CP 2 有可能成为治疗AD的药物。我们提出以下具体目标：（1）研究 在CP 2和类似物的存在下，A β 40和A β 42的结构变化和聚集状态;（2） CP 2阻断β-折叠形成和A β 40聚集的机制的鉴定， （3）含有C9、C11官能团的CP 2的新类似物TP的小文库的合成 和C14的体外生物活性的研究;（4）CP 2类似物在细胞培养物中的体外生物活性的研究;和（5）CP 2类似物在细胞培养物中的体内生物活性的研究。 CP 2类似物对3xTg-AD APP小鼠的药理学作用。这项建议的最终目标是 鉴定能够在动物模型中阻断Ab病变形成的先导化合物，这可能导致 用于治疗AD的药物。CP 2及其类似物在AD药物开发中具有巨大的潜力。 相关性：淀粉样β-肽的寡聚化已被证明是淀粉样β-肽的主要特征。 AD的发病机制单体Abeta在正常代谢过程中产生，似乎没有毒性， 对神经元的影响然而，可溶性寡聚Abeta显示出高神经元毒性。抑制 这些毒性可溶性Abeta寡聚体的形成将为AD提供治疗剂。

Alzheimer's disease (AD) is a progressive and irreversible brain disorder with no known cure. A small protein, amyloid beta peptide (Abeta) containing 39-43 amino acids, is widely considered a culprit for the disease. Recent evidence indicates that soluble oligomers of Abeta may represent the primary toxic species of amyloid in AD. It is accepted that newly produced Abeta is monomeric, soluble and non-toxic, adopting random coil/alpha-helix mixture structures under normal physiological conditions. In AD, Abeta undergoes conformational changes from random coil/alpha-helix to beta-sheet structure, resulting in oligomerization and precipitation. In search of a compound that blocks this conformational change, we discovered that a class of tricyclic pyrones (TP), especially CP2 (code name), prevents the death of human neuroblastoma MC65 cells related to intracellular accumulation of Abeta-containing metabolites. CP2 inhibits the aggregation of Abeta 1- 40 and Abeta1-42 peptides, blocks Abeta1-40 and Abeta1-42 beta-sheet formation, and binds to Abeta peptides in vitro. CP2 also penetrated blood-brain barrier in mice. These exciting results suggest that CP2 may potentially serve as a drug to treat AD. We propose the following specific aims: (1) Studies of the structural changes and aggregation states of Abeta40 and Abeta42 in the presence of CP2 and analogs; (2) Identification of the mechanism by which CP2 blocks beta-sheet formation and aggregation of Abeta40 and Abeta42; (3) Syntheses of a small library of TP, new analogs of CP2 containing functional groups at C9, C11 and C14; (4) Studies of the in vitro bioactivities of CP2 analogs in cell cultures; and (5) Studies of the in vivo pharmacological effect of CP2 analogs with 3xTg-AD APP mice. The ultimate goal of this proposal are to identify a lead compound that is able to block the formation of Ab lesions in animal model, which may lead to drugs for the treatment of AD. CP2 and its analogs should have great potential in AD drug development. Relevance: Oligomerization of amyloid beta-peptide has been shown to be a major feature of the pathogenesis of AD. Monomeric Abeta is produced during normal metabolism and appears to have no toxic effects on neurons. However, soluble oligomeric Abeta showed high neuronal toxicity. Inhibition of the formation of these toxic soluble Abeta oligomers would provide therapeutics for AD.