THE CARBOXY TERMINUS OF THE BETA-AMYLOID PROTEIN IS CRITICAL FOR THE SEEDING OF AMYLOID FORMATION - IMPLICATIONS FOR THE PATHOGENESIS OF ALZHEIMERS-DISEASE
THE CARBOXY TERMINUS OF THE BETA-AMYLOID PROTEIN IS CRITICAL FOR THE SEEDING OF AMYLOID FORMATION - IMPLICATIONS FOR THE PATHOGENESIS OF ALZHEIMERS-DISEASE
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DOI：
10.1021/bi00069a001
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发表时间：
1993-05-11
期刊：
影响因子：
2.9
通讯作者：
LANSBURY, PT
中科院分区：
文献类型：
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作者：
JARRETT, JT;BERGER, EP;LANSBURY, PT
β淀粉样蛋白的几种变体，仅在其羧基末端不同（β 1 -39、β 1 -40、β 1 -42和β 1 -43），已被鉴定为阿尔茨海默病特征性脑淀粉样蛋白沉积物的主要成分。三种天然β蛋白变体（β 1 -39、β 1 -40、β 1 -42）和四种模型肽（β 26 -39、β 26 -40、β 26 -42、β 26 -43）的聚集动力学研究表明，淀粉样蛋白形成与结晶一样，是一种成核依赖性现象。这一发现对β淀粉样蛋白的研究具有实际意义。 C-末端的长度是淀粉样蛋白形成速率（“动力学溶解度”）的关键决定因素，但对热力学溶解度只有很小的影响。通过动力学可溶性肽（例如，β 1 -39、β 1 -40、β 26 -39、β 26 -40）可以被包括关键C-末端残基（β 1 -42、β 26 -42、β 26 -43、β 34 -42）的肽成核或“接种”。这些结果表明，成核可能是体内淀粉样蛋白生成的速率决定步骤，β 1 -42和/或β 1 -43，而不是β 1 -40，可能是AD的致病蛋白。
Several variants of the beta amyloid protein, differing only at their carboxy terminus (beta1-39, beta1-40, beta1-42, and beta1-43), have been identified as the major components of the cerebral amyloid deposits which are characteristic of Alzheimer's disease. Kinetic studies of aggregation by three naturally occurring beta protein variants (beta1-39, beta1-40, beta1-42) and four model peptides (beta26-39, beta26-40, beta26-42, beta26-43) demonstrate that amyloid formation, like crystallization, is a nucleation-dependent phenomenon. This discovery has practical consequences for studies of the beta amyloid protein. The length of the C-terminus is a critical determinant of the rate of amyloid formation (''kinetic solubility'') but has only a minor effect on the thermodynamic solubility. Amyloid formation by the kinetically soluble peptides (e.g., beta1-39, beta1-40, beta26-39, beta26-40) can be nucleated, or ''seeded'', by peptides which include the critical C-terminal residues (beta1-42,beta26-42,beta26-43,beta34-42). These results suggest that nucleation may be the rate-determining step of in vivo amyloidogenesis and that beta1-42 and/or beta1-43, rather than beta1-40, may be the pathogenic protein(s) in AD.