Snyder S W, Ladror U S, Wade W S, Wang G T, Barrett L W, Matayoshi E D, Huffaker H J, Krafft G A, Holzman T F
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500.
Biophys J. 1994 Sep;67(3):1216-28. doi: 10.1016/S0006-3495(94)80591-0.
One of the clinical manifestations of Alzheimer's disease is the deposition of the 39-43 residue amyloid-beta (A beta) peptide in aggregated fibrils in senile plaques. Characterization of the aggregation behavior of A beta is one of the critical issues in understanding the role of A beta in the disease process. Using solution hydrodynamics, A beta was observed to form three types of species in phosphate-buffered saline: insoluble aggregates with sedimentation coefficients of approximately 50,000 S and molecular masses of approximately 10(9) Da, "soluble aggregates" with sedimentation coefficients of approximately 30 S and masses of approximately 10(6) Da, and monomer. When starting from monomer, the aggregation kinetics of A beta 1-40 (A beta 40) and A beta 1-42 (A beta 42), alone and in combination, reveal large differences in the tendency of these peptides to aggregate as a function of pH and other solution conditions. At pH 4.1 and 7.0-7.4, aggregation is significantly slower than at pH 5 and 6. Under all conditions, aggregation of the longer A beta 42 was more rapid than A beta 40. Oxidation of Met-35 to the sulfoxide in A beta 40 enhances the aggregation rate over that of the nonoxidized peptide. Aggregation was found to be dependent upon temperature and to be strongly dependent on peptide concentration and ionic strength, indicating that aggregation is driven by a hydrophobic effect. When A beta 40 and A beta 42 are mixed together, A beta 40 retards the aggregation of A beta 42 in a concentration-dependent manner. Shorter fragments have a decreasing ability to interfere with A beta 42 aggregation. Conversely, the rate of aggregation of A beta 40 can be significantly enhanced by seeding slow aggregating solutions with preformed aggregates of A beta 42. Taken together, the inhibition of A beta 42 aggregation by A beta 40, the seeding of A beta 40 aggregation by A beta 42 aggregates, and the chemical oxidation of A beta 40 suggest that the relative abundance and rates of production of different-length A beta and its exposure to radical damage may be factors in the accumulation of A beta in plaques in vivo.
阿尔茨海默病的临床表现之一是39 - 43个残基的β淀粉样蛋白（Aβ）肽在老年斑中的聚集纤维中沉积。表征Aβ的聚集行为是理解Aβ在疾病过程中作用的关键问题之一。利用溶液流体动力学方法，观察到Aβ在磷酸盐缓冲盐溶液中形成三种类型的聚集体：沉降系数约为50,000 S、分子量约为10⁹ Da的不溶性聚集体，沉降系数约为30 S、质量约为10⁶ Da的“可溶性聚集体”，以及单体。当从单体开始时，Aβ1 - 40（Aβ40）和Aβ1 - 42（Aβ42）单独及混合时的聚集动力学显示，这些肽作为pH和其他溶液条件的函数，其聚集倾向存在很大差异。在pH 4.1以及7.0 - 7.4时，聚集明显慢于pH 5和6时。在所有条件下，较长的Aβ42的聚集都比Aβ40更快。Aβ40中Met - 35氧化为亚砜会使其聚集速率比未氧化的肽更快。发现聚集依赖于温度，并且强烈依赖于肽浓度和离子强度，表明聚集是由疏水作用驱动的。当Aβ40和Aβ42混合在一起时，Aβ40以浓度依赖的方式延缓Aβ42的聚集。较短的片段干扰Aβ42聚集的能力逐渐降低。相反，通过用预先形成 的Aβ42聚集体接种缓慢聚集的溶液，Aβ40的聚集速率可以显著提高。综上所述，Aβ40对Aβ42聚集的抑制、Aβ42聚集体对Aβ40聚集的接种以及Aβ40的化学氧化表明，不同长度Aβ的相对丰度和产生速率及其暴露于自由基损伤可能是体内Aβ在斑块中积累的因素。
