Watson Desiree, Castaño Eduardo, Kokjohn Tyler A, Kuo Yu-Min, Lyubchenko Yuri, Pinsky David, Connolly E Sander, Esh Chera, Luehrs Dean C, Stine W Blaine, Rowse Linda M, Emmerling Mark R, Roher Alex E
Pfizer, Global Research and Development, Ann Arbor, MI 48106 USA.
Neurol Res. 2005 Dec;27(8):869-81. doi: 10.1179/016164105X49436.
Extracellular fibrillar amyloid deposits are prominent and universal Alzheimer's disease (AD) features, but senile plaque abundance does not always correlate directly with the degree of dementia exhibited by AD patients. The mechanism(s) and dynamics of Abeta fibril genesis and deposition remain obscure. Enhanced Abeta synthesis rates coupled with decreased degradative enzyme production and accumulating physical modifications that dampen proteolysis may all enhance amyloid deposit formation. Amyloid accumulation may indirectly exert the greatest pathologic effect on the brain vasculature by destroying smooth muscle cells and creating a cascade of negative impacts on cerebral blood flow. The most visible manifestation of amyloid dis-equilibrium could actually be a defense mechanism employed to avoid serious vascular wall degradation while the major toxic effects to the gray and white matter neurons are mediated by soluble oligomeric Abeta peptides with high beta-sheet content. The recognition that dynamic soluble oligomeric Abeta pools exist in AD and are correlated to disease severity led to neurotoxicity and physical conformation studies. It is now recognized that the most basic soluble Abeta peptides are stable dimers with hydrophobic regions sequestered from the aqueous environment and are capable of higher order aggregations. Time course experiments employing a modified ELISA method able to detect Abeta oligomers revealed dynamic intermolecular interactions and additional experiments physically confirmed the presence of stable amyloid multimers. Amyloid peptides that are rich in beta-sheet structure are capable of creating toxic membrane ion channels and a capacity to self-assemble as annular structures was confirmed in vitro using atomic force microscopy. Biochemical studies have established that soluble Abeta peptides perturb metabolic processes, provoke release of deleterious reactive compounds, reduce blood flow, induce mitochondrial apoptotic toxicity and inhibit angiogenesis. While there is no question that gross amyloid deposition does contribute to AD pathology, the destructive potential now associated with soluble Abeta suggests that treatment strategies that target these molecules may be efficacious in preventing some of the devastating effects of AD.
细胞外纤维状淀粉样沉积物是阿尔茨海默病（AD）的显著且普遍的特征，但老年斑的丰度并不总是与AD患者表现出的痴呆程度直接相关。β淀粉样蛋白（Aβ）纤维的生成和沉积机制及动力学仍不清楚。Aβ合成速率的提高，加上降解酶产生的减少以及抑制蛋白水解的累积物理修饰，都可能增强淀粉样沉积物的形成。淀粉样蛋白的积累可能通过破坏平滑肌细胞并对脑血流产生一系列负面影响，从而间接对脑血管系统产生最大的病理影响。淀粉样蛋白失衡最明显的表现实际上可能是一种防御机制，用于避免血管壁严重降解，而对灰质和白质神经元的主要毒性作用是由具有高β折叠含量的可溶性寡聚Aβ肽介导的。认识到AD中存在动态可溶性寡聚Aβ池且与疾病严重程度相关，引发了神经毒性和物理构象研究。现在人们认识到，最基本的可溶性Aβ肽是稳定的二聚体，其疏水区域与水环境隔离，并且能够进行更高阶的聚集。采用能够检测Aβ寡聚体的改良ELISA方法进行的时间进程实验揭示了动态分子间相互作用，并且其他实验从物理上证实了稳定淀粉样多聚体的存在。富含β折叠结构的淀粉样肽能够形成有毒的膜离子通道，并且使用原子力显微镜在体外证实了其自组装成环状结构的能力。生化研究表明，可溶性Aβ肽扰乱代谢过程，引发有害反应性化合物的释放，减少血流，诱导线粒体凋亡毒性并抑制血管生成。虽然毫无疑问，大量淀粉样蛋白沉积确实会导致AD病理，但现在与可溶性Aβ相关的破坏潜力表明，针对这些分子的治疗策略可能有效地预防AD的一些破坏性影响。
