Internalization of beta-amyloid causes downregulation of apolipoprotein E mRNA expression in neuroblastoma cells.
Apolipoprotein (apo) E, like beta-amyloid (Abeta), is a key component of the senile plaques that characterize Alzheimer's disease (AD). Understanding how apoE participates in the formation of senile plaques is necessary to clarify the pathogenesis of AD; however, the mechanism remains unknown. In this study, we investigated the changes of cellular apoE and its mRNA level induced by addition of extracellular Abeta to neuroblastoma cells. The presence of > or = 1.0 micromol/L of Abeta induced a decrease of apoE mRNA expression and an increase in the immunofluorescence reactivity for intracellular apoE. Both Abeta and apoE were observed by electron-microscopy to be localized within lysosomes. The levels of intracellular apoE and its mRNA returned to the steady state time-dependently. These changes were attenuated by treatments with heparinase I or receptor-associated protein. These findings suggest that the internalized Abeta, along with cellular apoE, induces downregulation of apoE mRNA via a pathway possibly mediated by apoE receptors and heparin sulfate proteoglycans. A disorder of this physiological response could be linked to the development of AD.
Yamauchi
Kazuyoshi
K
Department of Laboratory Medicine, Shinshu University Hospital and Medical School, Asahi, Matsumoto, Japan. yamauchi@hsp.md.shinshu-u.ac.jp
Tozuka
Minoru
M
Hidaka
Eiko
E
Ueno
Ichiro
I
Matsuda
Kazuyuki
K
Katsuyama
Tsutomu
T
D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics*; D001057:Apolipoproteins E / Q000235:genetics*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019763:Heparin Lyase / Q000494:pharmacology; D026563:LDL-Receptor Related Protein-Associated Protein / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008854:Microscopy, Electron; D009447:Neuroblastoma; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D012333:RNA, Messenger; D011973:Receptors, LDL; D019763:Heparin Lyase