Nature of the neurotoxic membrane actions of amyloid-β on hippocampal neurons in Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:35

Article

Sepulveda, Fernando J.¹  Fierro, Humberto²  Fernandez, Eduardo¹  Castillo, Carolina²  Peoples, Robert W.³  Opazo, Carlos²  Aguayo, Luis G.¹ 

[1] Univ Concepcion, Dept Physiol, Neurophysiol Lab, Concepcion, Chile

[2] Univ Concepcion, Dept Physiol, Lab Neurobiomet, Concepcion, Chile

[3] Marquette Univ, Lab Biomed Sci, Milwaukee, WI 53233 USA

关键词: A beta;    Alzheimer's disease;    Pore formation;    Membrane disruption;    A beta toxicity;   

DOI  :  10.1016/j.neurobiolaging.2013.08.035

来源: Elsevier

【 摘 要 】

The mechanism by which amyloid-beta (A beta b) produces brain dysfunction in patients with Alzheimer's disease is largely unknown. According to previous studies, A beta might share perforating properties with gramicidin, a well-accepted membrane-disrupting peptide. Therefore, we hypothesize that the key steps leading to synaptotoxicity by A beta and gramicidin involve peptide aggregation, pore formation, and calcium dysregulation. Here, we show that A beta and gramicidin form aggregates enriched in beta-sheet structures using electron microscopy, and Thioflavin and Congo Red staining techniques. Also, we found that A beta and gramicidin display fairly similar actions in hippocampal cell membranes, i.e. inducing Ca2+ entry and synaptoxicity characterized by the loss of synaptic proteins and a decrease in neuronal viability. These effects were not observed in a Ca2+ free solution, indicating that both A beta and gramicidin induce neurotoxicity by a Ca2+-dependent mechanism. Using combined perforated patch clamp and imaging recordings, we found that only A beta produced a perforation that progressed from a small (Cl--selective pore) to a larger perforation that allowed the entry of fluorescent molecules. Therefore, based on these results, we propose that the perforation at the plasma membrane by A beta is a dynamic process that is critical in producing neurotoxicity similar to that found in the brains of AD patients. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

Free