CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway
CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway
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DOI：
10.1074/jbc.ra118.005385
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发表时间：
2019-07-12
影响因子：
4.8
通讯作者：
Hisanaga, Shin-ichi
中科院分区：
文献类型：
--
作者：
Furusawa, Kotaro;Takasugi, Toshiyuki;Hisanaga, Shin-ichi
阿尔茨海默病(AD)病理的一个特征是出现老年斑，它由β-淀粉样蛋白(Aβ)多肽组成。β蛋白是由淀粉样前体蛋白(APP)在β-和伽马分泌酶作用下连续裂解而产生的。在APP通过内吞和循环途径在细胞内运输的过程中，这些裂解发生在内吞体内。全基因组关联研究已经确定了几个晚发性AD的危险因素，其中之一是CD2相关蛋白(CD2AP)，这是一种调节膜运输的适配器分子。尽管最近有报道称CD2AP参与了应用程序交易，但如何监管应用程序交易仍不清楚。我们试图通过研究CD2AP过表达或敲除对培养的COS-7和HEK293细胞内APP分布和APP降解的影响来解决这个问题。我们发现，CD2AP的过表达增加了APP对Rab7阳性的晚期内小体的定位，而减少了其对Rab5阳性的早期内小体的定位。CD2AP的过表达加速了APP的降解，但不影响其降解速率。此外，营养饥饿增加了APP在Rab7阳性晚期内小体的定位，CD2AP过表达刺激了饥饿诱导的溶酶体APP降解。此外，CD2AP在小鼠原代皮质神经元中的过度表达和下调证实了CD2AP对APP降解的影响。结论：CD2AP可加速APP从早期向晚期的转移。这种本地化的转移通过减少降解开始之前的时间量来刺激APP的降解。综上所述，这些结果可能解释了为什么CD2AP功能受损是AD的危险因素。
A hallmark of Alzheimer's disease (AD) pathology is the appearance of senile plaques, which are composed of beta-amyloid (A beta) peptides. A beta is produced by sequential cleavages of amyloid precursor protein (APP) by beta- and gamma-secretases. These cleavages take place in endosomes during intracellular trafficking of APP through the endocytic and recycling pathways. Genome-wide association studies have identified several risk factors for late-onset AD, one of which is CD2-associated protein (CD2AP), an adaptor molecule that regulates membrane trafficking. Although CD2AP's involvement in APP trafficking has recently been reported, how APP trafficking is regulated remains unclear. We sought to address this question by investigating the effect of CD2AP overexpression or knockdown on the intracellular APP distribution and degradation of APP in cultured COS-7 and HEK293 cells. We found that overexpression of CD2AP increases the localization of APP to Rab7-positive late endosomes, and decreases its localization to Rab5-positive early endosomes. CD2AP overexpression accelerated the onset of APP degradation without affecting its degradation rate. Furthermore, nutrient starvation increased the localization of APP to Rab7-positive late endosomes, and CD2AP overexpression stimulated starvation-induced lysosomal APP degradation. Moreover, the effect of CD2AP on the degradation of APP was confirmed by CD2AP overexpression and knockdown in primary cortical neurons from mice. We conclude that CD2AP accelerates the transfer of APP from early to late endosomes. This transfer in localization stimulates APP degradation by reducing the amount of time before degradation initiation. Taken together, these results may explain why impaired CD2AP function is a risk factor for AD.