The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation
The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation
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DOI：
10.1038/nn0901-887
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发表时间：
2001-09-01
影响因子：
25
通讯作者：
Lannfelt, L
中科院分区：
文献类型：
--
作者：
Nilsberth, C;Westlind-Danielsson, A;Lannfelt, L
已经描述了几种致病性阿尔茨海默病（AD）突变，所有这些突变都导致淀粉样β蛋白（A β）水平增加。在这里，我们目前的研究致病性淀粉样前体蛋白（APP）突变，位于A β序列密码子693（E693G），导致AD在瑞典家庭。这种“北极”突变的携带者显示血浆中A β 42和A β 40水平降低。此外，在来自用APP（E693G）转染的细胞的条件培养基中检测到低水平的A β 42。纤维化研究表明纤维化率没有差异，但具有北极突变的A β以比野生型（wt）A β高得多的速率和更大的量形成原纤维。在北极AD中发现的原纤维形成增加和A β血浆水平降低可能反映了AD的另一种致病机制，涉及快速A β原纤维形成，导致细胞内和/或细胞外不溶性A β的加速积聚。
Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta -protein (A beta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the A beta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased A beta 42 and A beta 40 levels in plasma. Additionally, low levels of A beta 42 were detected in conditioned media from cells transfected with APP(E693G). Fibrillization studies demonstrated no difference in fibrillization rate, but A beta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) A beta. The finding of increased protofibril formation and decreased A beta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid A beta protofibril formation leading to accelerated buildup of insoluble A beta intra- and/or extracellularly.