Affiliations:
Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Chile
Correspondence:
[*]
Correspondence to: Dr. Luis G. Aguayo, Department of Physiology, University of Concepción, P.O. Box 160-C, Concepción, Chile. Tel.: +56 41 2203380; Fax: +56 41 2245975; E-mail: laguayo@udec.cl.
Note: [1] Present address: Oxidation Biology Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia.
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 Aβ1 - 42; Aβ1 - 28 from the N-terminal region, Aβ25 - 35 from the central region, and Aβ17 - 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 Aβ1 - 28 contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; Aβ25 - 35 is important for membrane perforation, calcium increase, and synaptotoxicity; and Aβ17 - 42 induced mitochondrial toxicity similar to the full length Aβ1 - 42, but was unable to induce membrane perforation and calcium increase, supporting the idea that it is less toxic in the non-amyloidogenic pathway.
