Differential Membrane Toxicity of Amyloid-β Fragments by Pore Forming Mechanisms

A major characteristic of Alzheimer's disease (AD) is the presence of amyloid-beta peptide (A beta) oligomers and aggregates in the brain. It is known that A beta 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 A beta exerts its effect on the plasma membrane, we evaluated three A beta fragments derived from different regions of A beta(1-42); A beta(1-28) from the N-terminal region, A beta(25-35) from the central region, and A beta(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 A beta(1-28) contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; A beta(25-35) is important for membrane perforation, calcium increase, and synaptotoxicity; and A beta(17-42) induced mitochondrial toxicity similar to the full length A beta(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.