Cross-linking of cell surface amyloid precursor protein leads to increased β-amyloid peptide production in hippocampal neurons: implications for Alzheimer's disease.
Cross-linking of cell surface amyloid precursor protein leads to increased β-amyloid peptide production in hippocampal neurons: implications for Alzheimer's disease.
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DOI：
10.1523/jneurosci.6473-11.2012
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发表时间：
2012-08-01
期刊：
影响因子：
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通讯作者：
Shelanski M
中科院分区：
文献类型：
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作者：
Lefort R;Pozueta J;Shelanski M
β-淀粉样肽（Aβ）在阿尔茨海默病（AD）中的积累被认为在触发神经元中的突触功能障碍中起致病作用，导致其最终通过凋亡而死亡。Aβ在淀粉样前体蛋白（APP）被β-和γ-分泌酶连续裂解后产生和分泌。然而，虽然AD患者大脑中的Aβ水平已被证明增加，但对APP的切割和随后产生的Aβ如何受到影响，或者切割过程是否随时间而变化知之甚少。已经提出Aβ可以结合APP并促进APP的淀粉样蛋白加工，进一步增强Aβ的产生。由于缺乏明确的机制以及Aβ结合的混杂性质，这一想法仍然存在争议。为了解决这个问题，我们使用抗体介导的方法在培养的大鼠原代海马神经元中结合和交联细胞表面APP。在这里，我们发现APP的交联足以提高存活神经元中Aβ的水平，同时β-分泌酶BACE 1的水平也随之增加。这似乎是由于分选缺陷而发生的，这是由于胱天蛋白酶-3介导的关键分选衔接蛋白（即GGA 3）的失活，GGA 3阻止了BACE 1的溶酶体降解。综上所述，我们的数据表明，在受影响的神经元中发生了涉及Aβ和APP的阳性致病反馈回路，可能允许Aβ扩散到附近的健康神经元。
The accumulation of the β-amyloid peptide (Aβ) in Alzheimer’s disease (AD) is thought to play a causative role in triggering synaptic dysfunction in neurons leading to their eventual demise through apoptosis. Aβ is produced and secreted upon sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, while Aβ levels have been shown to be increased in AD patients’ brains, little is known about how the cleavage of APP and the subsequent generation of Aβ is influenced, or if the cleavage process changes over time. It has been proposed that Aβ can bind APP and promote amyloidogenic processing of APP, further enhancing Aβ production. This idea has remained controversial due to a lack of a clear mechanism and complicated by the promiscuous nature of Aβ binding. To work around this problem, we used an antibody-mediated approach to bind and cross-link cell surface APP in cultured rat primary hippocampal neurons. Here we show that cross-linking of APP is sufficient to raise the levels of Aβ in viable neurons with a concomitant increase in the levels of the β-secretase BACE1. This appears to occur as a result of a sorting defect, due to the caspase-3-mediated inactivation of a key sorting adaptor protein, namely GGA3, which prevents the lysosomal degradation of BACE1. Taken together, our data suggest the occurrence of a positive pathogenic feedback loop involving Aβ and APP in affected neurons possibly allowing Aβ to spread to nearby healthy neurons.