Fe3+ Facilitates Endocytic Internalization of Extracellular A beta(1-42) and Enhances A beta(1-42)-Induced Caspase-3/Caspase-4 Activation and Neuronal Cell Death

作者：Nishizaki, Tomoyuki^*

来源：Molecular Neurobiology, 2019, 56(7): 4812-4819.

DOI：10.1007/s12035-018-1408-y

• Amyloid beta(1-42)
• Fe3+
• Internalization
• Endocytosis
• Neuronal cell death
• Caspase activation

Amyloid beta (A beta) peptide is a critical causative factor in Alzheimer's disease (AD) and of a variety of fragmented A beta peptides A beta-1-42 thought to exhibit the most neurotoxic effect. The present study investigated the effects of Fe3+ on A beta 1-42 internalization and A beta-1-42-induced caspase activation and neurotoxicity using mouse hippocampal slices and cultured PC-12 cells. Extracellularly applied A beta 1-42 increased the cell-associated A beta 1-42 levels in a concentration-dependent manner, and the effect was enhanced by adding Fe3+. Fe3+induced enhancement of the cell-associatedA beta 1-42 levels was significantly inhibited by the endocytosis inhibitors dynasore andmethyl-beta cyclodextrin. A beta 1-42 reduced PC-12 cell viability in a concentration-dependent manner, and further reduction of the cell viability was obtained with Fe3+. A beta 1-42-induced reduction of cell viability was not affected by A187, an antagonist of amylin-3 receptor. A beta 1-42 activated caspase-3, caspase-4, and caspase-8 to a variety of degrees and Fe3+ further enhancedA beta 1-42-induced activation of caspase-3 and caspase-4. Taken together, these results indicate that Fe3+ accelerates endocytic internalization of extracellular A beta 1-42, enhances A beta 1-42induced caspase-3/ caspase-4 activation, and promotes A beta 1-42-induced neuronal cell death, regardless of amylin receptor.

• 出版日期2019-7
• 单位上海中医药大学