Oligomerisation differentially affects the acute and chronic actions of amyloid-β in vitro
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Key neuropathological hallmarks of Alzheimer's disease include the accumulation of amyloid-beta (A beta), disruption of Ca2+ homeostasis and neurodegeneration. However, the physical nature of the toxic A beta species is controversial. Here, we examined the effect of aging on acute and chronic actions of A beta peptides: changes in intracellular Ca2+ and toxic responses, respectively. Acute application of A beta(1-42) to PC12 cells potentiated KCl-evoked increases in Ca2+, while chronic application decreased mitochondrial function with concomitant perturbation of membrane integrity and activation of apoptosis in PC12 cells, and reduced neurite length and synaptogenesis in rat cortical neurons. Both the acute and chronic effects of A beta(1-42) were prevented by the anti-oligomerisation peptide D-KLVFFA, implicating oligomeric structures. The generation of a range of oligomeric species by aging A beta(1-42) at 37 degrees C for different times was supported by thioflavin T fluorescence and atomic force microscopy. A beta(1-42) aged for 24 h maximally potentiated KCl-evoked increases in Ca2+, and this correlated with oligomers composed of 3-6 monomers, as judged by size exclusion filtration. Aging for 72 or 96 h, which generated fibrillar structures, was less efficacious. The A beta(25-35) fragment that lacks the self-recognition element targeted by D-KLVFFA failed to potentiate KCl-evoked increases in Ca2+. However, A beta(25-35) was more efficacious than A beta(1-42) at decreasing cellular functions when applied chronically. The acute and chronic effects of A beta(1-42) also showed differential sensitivity to blockade of voltage operated Ca2+ channels. These results suggest that the acute effects of A beta(1-42) on Ca2+ signals do not underpin the toxic responses measured, although both acute and chronic effects are promoted by small oligomeric species.
|Creators||Innocent, N., Evans, N., Hille, C. and Wonnacott, S.|
|Uncontrolled Keywords||thioflavin t, pc12 cells, synaptogenesis, intracellular ca2+, atomic force microscopy, cortical neurons|
|Departments||Faculty of Science > Biology & Biochemistry|
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