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An Aβ42 double mutant inhibits Aβ42-induced plasma and mitochondrial membrane disruption in artificial membranes, isolated organs and intact cells.

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Destabilization of plasma and inner mitochondrial membranes by extra- and intracellular amyloid β peptide (Aβ42) aggregates may lead to dysregulated calcium flux through the plasma membrane, mitochondrial-mediated apoptosis and neuronal… Click to show full abstract

Destabilization of plasma and inner mitochondrial membranes by extra- and intracellular amyloid β peptide (Aβ42) aggregates may lead to dysregulated calcium flux through the plasma membrane, mitochondrial-mediated apoptosis and neuronal cell death in patients with Alzheimer's disease. In the current study, experiments performed with artificial membranes, isolated mitochondria, and neuronal cells allowed us to understand the mechanism by which a non-aggregating Aβ42 double mutant (designated Aβ42DM) exerts its neuro-protective effects. Specifically, we showed that Aβ42DM protected neuronal cells from Aβ42-induced accumulation of toxic intracellular levels of calcium and from apoptosis. Aβ42DM also inhibited Aβ42-induced mitochondrial membrane potential depolarization in the cells and abolished the Aβ42-mediated decrease in cytochrome C oxidase activity in purified mitochondrial particles. These results can be explained in terms of the amelioration by Aβ42DM of Aβ42-mediated changes in membrane fluidity in DOPC and cardiolipin/DOPC phospholipid vesicles, mimicking plasma and mitochondrial membranes, respectively. These observations are also in agreement with the inhibition by Aβ42DM of phospholipid-induced conformational changes in Aβ42 and with the fact that, unlike Aβ42, neither Aβ42DM nor anthe Aβ42-Aβ42DM complex could not permeate into cells, but instead remained attached to the cell membrane. Although most of the Aβ42DM molecules were localized on the cell membrane, some penetrated into the cytosol in an Aβ42-independent process, and, unlike Aβ42, did not form intracellular inclusion bodies. Overall, we provide a mechanistic explanation for the inhibitory activity of Aβ42DM against Aβ42-induced membrane permeability and cell toxicity and provide confirmatory evidence for its protective function in neuronal cells.

Keywords: membranes isolated; artificial membranes; plasma mitochondrial; mitochondrial membrane; membrane; double mutant

Journal Title: ACS chemical neuroscience
Year Published: 2020

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