title: Differential Membrane Toxicity of Amyloid-β Fragments by Pore Forming Mechanisms.
abstract: A major characteristic of Alzheimer's disease (AD) is the presence of amyloid-β peptide (Aβ) oligomers and aggregates in the brain. It is known that Aβ oligomers interact with the neuronal membrane and induce perforations that cause an influx of calcium ions and enhance the release of synaptic vesicles leading to a delayed synaptic failure by vesicle depletion. To better understand the mechanism by which Aβ exerts its effect on the plasma membrane, we evaluated three Aβ fragments derived from different regions of Aβ(1-42); Aβ(1-28) from the N-terminal region, Aβ(25-35) from the central region, and Aβ(17-42) from the C-terminal region. The neuronal activities of these fragments were examined with patch clamp, immunofluorescence, transmission electron microscopy, aggregation assays, calcium imaging, and MTT reduction assays. The present results indicate that the fragment Aβ(1-28) contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; Aβ(25-35) is important for membrane perforation, calcium increase, and synaptotoxicity; and Aβ(17-42) induced mitochondrial toxicity similar to the full length Aβ(1-42), but was unable to induce membrane perforation and calcium increase, supporting the idea that it is less toxic in the non-amyloidogenic pathway.
authors.forename: Christian
authors.initials: C
authors.lastname: Peters
authors.forename: Denisse
authors.initials: D
authors.lastname: Bascuñán
authors.forename: Carlos
authors.initials: C
authors.lastname: Opazo
authors.forename: Luis G
authors.initials: LG
authors.lastname: Aguayo
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000633:toxicity*; D016062:Porosity; D017207:Rats, Sprague-Dawley; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C086839:amyloid beta-protein (17-42); D002118:Calcium
keywords: Alzheimer’s disease; amyloid; membranes; peptides; pore