P017 - MEMBRANE COMPOSITION CAN MODULATE CELLULAR RESILIENCY TO AMYLOID-BETA42 OLIGOMER TOXICITY (ID 983)
Abstract
Aims
Protein misfolded oligomers comprised of the 42-residue form of the amyloid-β peptide (Aβ42) are thought to play a key role in the onset and development of Alzheimer’s disease. These metastable and heterogenous aggregates interact with a wide range of phospholipids and receptors in the cellular membrane, therein disrupting membrane integrity and ion homeostasis. A more detailed understanding of the nature of this deleterious interaction would give valuable insight into drug discovery targets within the cell membrane to combat oligomer toxicity.
Methods
Using cellular assays to quantify the integrity and viability of SH-SY5Y human neuroblastoma cells, we examined the resiliency of cells enriched with differing concentrations of key membrane lipids to Aβ42 oligomers, such as cholesterol, sphingolipids, ceramides, and other integral molecules. Additionally, we examined the effectiveness of a steroid polyamine countermeasure on cells with differing membrane compositions in neurotoxic conditions.
Results
As monitored using MTT assays and confocal microscopy, we observed changes in the toxicity of Aβ42 oligomers upon cellular enrichment in specific membrane lipids, indicating that Aβ42 oligomers may interact preferentially with certain regions of the cellular membrane. Moreover, we observed that a brain permeable aminosterol could attenuate the toxicity of the oligomers, a finding that was largely independent of the lipid enrichment conditions.
Conclusions
These findings indicate that a molecular countermeasure which competes with oligomers for interactions in certain regions of the plasma membrane may be effective at preventing cell death in Alzheimer’s disease.
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