Beyreuther K, Multhaup G, Masters C L
ZMBH, Center for Molecular Biology, University of Heidelberg, Germany.
Ciba Found Symp. 1996;199:119-27; discussion 127-31.
Much of the present knowledge on the genes and genetic processes involved in the genesis of amyloid formation in Alzheimer's disease (AD) has come directly or indirectly from the retrospective molecular and genetic analysis of amyloid beta-protein (A beta or beta A4) deposits and from the identification of genes involved in inherited susceptibility to the disease. This analysis shows that the release and aggregation of the A beta fragment from the amyloid precursor protein (APP) is involved in APP (AD1), chromosome 14 (AD3), 1 (AD4) and 19(AD2) families as well as in the sporadic forms of AD, suggesting that AD is a single disease with a common APP/A beta amyloid pathogenesis. Synthetic A beta protein readily forms beta sheets, filaments and amyloid at micromolar concentrations. The principle to inhibit this process has been worked out by our groups with A beta variants. The N-terminal and C-terminal A beta sequences, oxidative radicals, membrane integrity and metal ions also affect the aggregation of A beta. Amino acid substitutions within the A beta sequence, as occur in rodents, alter A beta release and change the degree to which oxidation of the peptides occurs. Transgenic approaches resulting in overexpression of human APP have confirmed that A beta sequence and concentration are critical prerequisites to amyloid deposition in vivo.
目前关于阿尔茨海默病（AD）淀粉样蛋白形成过程中涉及的基因和遗传过程的许多知识，直接或间接地来自于对淀粉样β蛋白（Aβ或βA4）沉积物的回顾性分子和遗传分析，以及对与该疾病遗传易感性相关基因的鉴定。该分析表明，淀粉样前体蛋白（APP）释放和Aβ片段聚集与APP（AD1）、14号染色体（AD3）、1号染色体（AD4）和19号染色体（AD2）家族以及散发性AD形式有关，这表明AD是一种具有共同APP/Aβ淀粉样蛋白发病机制的单一疾病。合成Aβ蛋白在微摩尔浓度下很容易形成β折叠、细丝和淀粉样蛋白。我们的研究小组利用Aβ变体已经找出了抑制这一过程的原理。Aβ的N端和C端序列、氧化自由基、膜完整性和金属离子也会影响Aβ的聚集。如在啮齿动物中出现的Aβ序列内的氨基酸替换，会改变Aβ的释放，并改变肽段氧化的程度。导致人类APP过表达的转基因方法证实，Aβ序列和浓度是体内淀粉样蛋白沉积的关键先决条件。
