title: Synaptotoxicity of Alzheimer beta amyloid can be explained by its membrane perforating property.
abstract: The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the development of disease-modifying therapies. One working hypothesis of AD is that Abeta excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes. Here we show that similar to other pore forming toxins, Abeta induces perforation of neuronal membranes causing an increase in membrane conductance, intracellular calcium and ethidium bromide influx. These data reveal that the target of Abeta is not another membrane protein, but that Abeta itself is the cellular target thereby explaining the failure of current therapies to interfere with the course of AD. We propose that this novel effect of Abeta could be useful for the discovery of anti AD drugs capable of blocking these "Abeta perforates". In addition, we demonstrate that peptides that block Abeta neurotoxicity also slow or prevent the membrane-perforating action of Abeta.
authors.affiliation: Laboratory of Neurophysiology, Department of Physiology, University of Concepción, Concepción, Chile.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Sepulveda
authors.forename: Jorge
authors.initials: J
authors.lastname: Parodi
authors.forename: Robert W
authors.initials: RW
authors.lastname: Peoples
authors.forename: Carlos
authors.initials: C
authors.lastname: Opazo
authors.forename: Luis G
authors.initials: LG
authors.lastname: Aguayo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D010455:Peptides; D002118:Calcium