Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking.
Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking.
复制标题
DOI：
10.1371/journal.pone.0011884
复制
发表时间：
2010-07-29
期刊：
影响因子：
3.7
通讯作者：
Bu G
中科院分区：
文献类型：
--
作者：
Fuentealba RA;Liu Q;Zhang J;Kanekiyo T;Hu X;Lee JM;LaDu MJ;Bu G
阿尔茨海默病（Alzheimer's disease，AD）是一种以神经元内淀粉样蛋白β 42（amyloid-β 42，Aβ42）沉积为特征的疾病。假设内体/溶酶体功能障碍可能与脑内细胞内Aβ42的病理性蓄积相关。我们以前的研究结果表明，LDL受体相关蛋白1（LRP 1），载脂蛋白E的主要受体，促进神经元内Aβ42在小鼠脑中的积累。然而，缺乏神经元通过LRP 1内吞Aβ42的直接证据。我们发现LRP 1的内吞功能是神经元摄取Aβ42所必需的。功能性LRP 1小受体mLRP 4的过表达可增加神经元溶酶体中Aβ42的摄取和蓄积。相反，LRP 1表达的敲低显著降低神经元Aβ42摄取。通过敲除网格蛋白或去除其胞质尾破坏LRP 1的内吞功能，可降低神经元中Aβ42的摄取和蓄积。最后，我们发现LRP 1介导的Aβ42神经元蓄积与细胞毒性增加相关。这些结果表明，LRP 1的内吞功能在神经元溶酶体中Aβ42的摄取和蓄积中起重要作用。这些发现强调了LRP 1在神经元Aβ代谢中的中枢作用。
Alzheimer's disease (AD) is characterized by the presence of early intraneuronal deposits of amyloid-β 42 (Aβ42) that precede extracellular amyloid deposition in vulnerable brain regions. It has been hypothesized that endosomal/lysosomal dysfunction might be associated with the pathological accumulation of intracellular Aβ42 in the brain. Our previous findings suggest that the LDL receptor-related protein 1 (LRP1), a major receptor for apolipoprotein E, facilitates intraneuronal Aβ42 accumulation in mouse brain. However, direct evidence of neuronal endocytosis of Aβ42 through LRP1 is lacking. Here we show that LRP1 endocytic function is required for neuronal Aβ42 uptake. Overexpression of a functional LRP1 minireceptor, mLRP4, increases Aβ42 uptake and accumulation in neuronal lysosomes. Conversely, knockdown of LRP1 expression significantly decreases neuronal Aβ42 uptake. Disruptions of LRP1 endocytic function by either clathrin knockdown or by removal of its cytoplasmic tail decreased both uptake and accumulation of Aβ42 in neurons. Finally, we show that LRP1-mediated neuronal accumulation of Aβ42 is associated with increased cellular toxicity. These results demonstrate that LRP1 endocytic function plays an important role in the uptake and accumulation of Aβ42 in neuronal lysosomes. These findings emphasize the central function of LRP1 in neuronal Aβ metabolism.
登录
查看更多内容
影响因子：
2.9
作者：
Burdick, D;Kosmoski, J;Glabe, CG
通讯作者：
Glabe, CG
影响因子：
4.8
作者：
Fuentealba, Rodrigo A.;Liu, Qiang;Bu, Guojun
通讯作者：
Bu, Guojun
影响因子：
34.7
作者：
Bu, Guojun
通讯作者：
Bu, Guojun
DOI：
10.1073/pnas.0911281106
发表时间：
2009-12-01
影响因子：
11.1
作者：
Hu, Xiaoyan;Crick, Scott L.;Lee, Jin-Moo
通讯作者：
Lee, Jin-Moo
影响因子：
9.3
作者：
Bu, GJ;Marzolo, MP
通讯作者：
Marzolo, MP