Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts.
Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts.
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DOI：
10.1083/jcb.200207113
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发表时间：
2003-01-06
期刊：
影响因子：
--
通讯作者：
Simons K
中科院分区：
文献类型：
--
作者：
Ehehalt R;Keller P;Haass C;Thiele C;Simons K
阿尔茨海默病(AD)的一个不变特征是形成含有淀粉样前体蛋白(β前体蛋白，APP)的淀粉样多肽(A-β)的老年斑。APP被β-分泌酶或α-分泌酶切割，分别启动APP的淀粉样变性(释放Aβ)或非淀粉样变性加工。理解AD的关键是解开这些酶对APP的访问是如何调节的。在这里，我们证明了脂筏在调节Aβ生成方面起着至关重要的作用。降低N2a细胞中的胆固醇水平会减少Aβ的产生。APP和β位点APP裂解酶(BACE1)与抗体发生交联后，可与质膜结合，并与非RAFT标志分离。抗体交联以胆固醇依赖的方式显著增加Aβ的产生。β的生成依赖于内吞作用，并且在动态蛋白突变体K44A和Rab5GTP酶激活蛋白RN-TrE表达后减少。这种抑制作用可以通过抗体交联来克服。这些观察结果表明，存在两个应用程序池。尽管RAFT集群内的APP似乎被β-分泌酶切割，但RAFT外的APP却经历了α-分泌酶的切割。因此，α-和β-分泌酶对APP的访问，从而产生β，可能是由APP与脂筏的动态相互作用决定的。
Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.
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