Mitogen-activated protein kinase signaling pathways promote low-density lipoprotein receptor-related protein 1-mediated internalization of beta-amyloid protein in primary cortical neurons.
Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD) are caused by the intraneuronal accumulation of beta-amyloid protein (Aβ). Reuptake of extracellular Aβ is believed to contribute significantly to the intraneuronal Aβ pool in the early stages of AD. Published reports have claimed that the low-density lipoprotein receptor-related protein 1 (LRP1) mediates Aβ1-42 uptake and lysosomal trafficking in GT1-7 neuronal cells and mouse embryonic fibroblast non-neuronal cells. However, there is no direct evidence supporting the role of LRP1 in Aβ internalization in primary neurons. Our recent study indicated that p38 MAPK and ERK1/2 signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor (α7nAChR)-mediated Aβ1-42 uptake in SH-SY5Y cells. This study was designed to explore the regulation of MAPK signaling pathways on LRP1-mediated Aβ internalization in neurons. We found that extracellular Aβ1-42 oligomers could be internalized into endosomes/lysosomes and mitochondria in cortical neurons. Aβ1-42 and LRP1 were also found co-localized in neurons during Aβ1-42 internalization, and they could form Aβ1-42-LRP1 complex. Knockdown of LRP1 expression significantly decreased neuronal Aβ1-42 internalization. Finally, we identified that p38 MAPK and ERK1/2 signaling pathways regulated the internalization of Aβ1-42 via LRP1. Therefore, these results demonstrated that LRP1, p38 MAPK and ERK1/2 mediated the internalization of Aβ1-42 in neurons and provided evidence that blockade of LRP1 or inhibitions of MAPK signaling pathways might be a potential approach to lowering brain Aβ levels and served a potential therapeutic target for AD.
Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
Wei-Na
WN
Yang
Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
Kai-Ge
KG
Ma
Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China. Electronic address: qianyh38@mail.xjtu.edu.cn.
Yi-Hua
YH
Qian
Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
Jian-Shui
JS
Zhang
Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
Gai-Feng
GF
Feng
Department of Human Anatomy, Xi'an Medical University, 1 Xinwang Road, Xi'an 710021, China.
Li-Li
LL
Shi
Department of Human Anatomy, Histology and Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an 710061, China.
Zhi-Chao
ZC
Zhang
Department of Anatomy and Cytoneurobiology Unit, Medical College of Soochow University, Suzhou 215123, China.
Zhao-Hui
ZH
Liu
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons; D010446:Peptide Fragments / Q000378:metabolism*; D061251:Primary Cell Culture; D021381:Protein Transport; D011973:Receptors, LDL / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010446:Peptide Fragments; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C075222:amyloid beta-protein (1-42)
Alzheimer's disease; Beta-amyloid protein; Internalization; Low-density lipoprotein receptor-related protein 1; Mitogen-activated protein kinase signaling pathways