Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake.
Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake.
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DOI：
10.1523/jneurosci.5491-10.2011
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发表时间：
2011-02-02
期刊：
影响因子：
--
通讯作者：
Bu G
中科院分区：
文献类型：
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作者：
Kanekiyo T;Zhang J;Liu Q;Liu CC;Zhang L;Bu G
阿尔茨海默病（Alzheimer's disease，AD）是一种进行性、不可逆的神经退行性疾病，其发病机制主要是β淀粉样蛋白（amyloid-β，Aβ）在脑内的聚集和沉积。在健康的大脑中，Aβ被有效代谢，几乎没有蓄积。Aβ的细胞摄取和随后的降解是其在脑中清除的主要途径之一。越来越多的证据表明，低密度脂蛋白受体相关蛋白1（LRP 1）在神经元、胶质细胞和沿着脑血管的Aβ代谢中发挥重要作用。硫酸乙酰肝素蛋白聚糖（HSPG）也与AD的几种致病特征有关，包括其与淀粉样斑块的共定位。在这里，我们证明了HSPG和LRP 1协同介导细胞Aβ摄取。荧光激活细胞分选仪和共聚焦显微镜显示，LRP 1的敲低抑制Aβ摄取，而LRP 1的过表达增强了神经细胞中的这一过程。HSPG拮抗剂肝素可显著抑制细胞Aβ摄取。重要的是，用肝素或肝素酶处理阻断了LRP 1介导的Aβ细胞摄取。我们进一步表明，HSPG对Aβ与细胞表面的结合比LRP 1更重要。在HSPG基因缺陷的中国仓鼠卵巢细胞中证实了HSPG在细胞Aβ结合和摄取中的关键作用。我们还发现，肝素和LRP 1的中和抗体抑制了原代神经元中的Aβ摄取。我们的研究结果表明，LRP 1和HSPG以合作的方式介导细胞Aβ摄取，并定义了Aβ进入神经元细胞的主要途径。
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder in which the aggregation and deposition of amyloid-β (Aβ) peptides in the brain are central to its pathogenesis. In healthy brains, Aβ is effectively metabolized with little accumulation. Cellular uptake and subsequent degradation of Aβ is one of the major pathways for its clearance in the brain. Increasing evidence has demonstrated significant roles for the low-density lipoprotein receptor-related protein 1 (LRP1) in the metabolism of Aβ in neurons, glia cells, and along the brain vasculatures. Heparan sulphate proteoglycan (HSPG) has also been implicated in several pathogenic features of AD, including its co-localization with amyloid plaques. Here, we demonstrate that HSPG and LRP1 cooperatively mediate cellular Aβ uptake. Fluorescence-activated cell sorter and confocal microscopy revealed that knockdown of LRP1 suppresses Aβ uptake while over-expression of LRP1 enhances this process in neuronal cells. Heparin, which antagonizes HSPG, significantly inhibited cellular Aβ uptake. Importantly, treatment with heparin or heparinase blocked LRP1-mediated cellular uptake of Aβ. We further showed that HSPG is more important for the binding of Aβ to the cell surface than LRP1. The critical roles of HSPG in cellular Aβ binding and uptake were confirmed in Chinese hamster ovary cells genetically deficient in HSPG. We also showed that heparin and a neutralizing antibody to LRP1 suppressed Aβ uptake in primary neurons. Our findings demonstrate that LRP1 and HSPG function in a cooperative manner to mediate cellular Aβ uptake and define a major pathway through which Aβ gains entry to neuronal cells.