Neuronal membrane cholesterol loss enhances amyloid peptide generation.
Neuronal membrane cholesterol loss enhances amyloid peptide generation.
复制标题
神经元膜胆固醇损失增强了淀粉样蛋白肽的产生。
DOI：
10.1083/jcb.200404149
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发表时间：
2004-12-06
影响因子：
7.8
通讯作者：
Dotti, Carlos G
中科院分区：
文献类型：
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作者：
Abad-Rodriguez, Jose;Ledesma, Maria Dolores;Craessaerts, Katleen;Perga, Simona;Medina, Miguel;Delacourte, Andre;Dingwall, Colin;De Strooper, Bart;Dotti, Carlos G
最近的实验和临床回顾性研究支持这样的观点，即降低脑胆固醇可以预防阿尔茨海默病（AD）。然而，遗传和药理学证据表明，低脑胆固醇导致神经退行性变。这一明显的矛盾促使我们在与生理和病理情况非常相似的实验系统中分析神经元胆固醇在淀粉样肽生成中的作用。我们发现，在对照人类和转基因小鼠的海马中，在相同的膜环境中，仅发现少量内源性APP及其β-分泌酶BACE 1。在AD患者的海马膜或啮齿动物海马神经元中发现了高得多的BACE 1-APP共定位水平，其中膜胆固醇中度降低。它们的共定位增加与淀粉样肽的产生增加有关。这些结果表明，神经元膜胆固醇的损失有助于过度淀粉样蛋白在AD和铺平了道路，为确定胆固醇损失的原因，并制定具体的治疗策略。
Recent experimental and clinical retrospective studies support the view that reduction of brain cholesterol protects against Alzheimer's disease (AD). However, genetic and pharmacological evidence indicates that low brain cholesterol leads to neurodegeneration. This apparent contradiction prompted us to analyze the role of neuronal cholesterol in amyloid peptide generation in experimental systems that closely resemble physiological and pathological situations. We show that, in the hippocampus of control human and transgenic mice, only a small pool of endogenous APP and its β-secretase, BACE 1, are found in the same membrane environment. Much higher levels of BACE 1–APP colocalization is found in hippocampal membranes from AD patients or in rodent hippocampal neurons with a moderate reduction of membrane cholesterol. Their increased colocalization is associated with elevated production of amyloid peptide. These results suggest that loss of neuronal membrane cholesterol contributes to excessive amyloidogenesis in AD and pave the way for the identification of the cause of cholesterol loss and for the development of specific therapeutic strategies.