Alzheimer's: A Proposed Mechanism for Amyloid Beta Toxicity

James Hall, UC Irvine

Amyloid has long been considered a major suspect as a causative agent for Alzheimer's disease, but the mechanisms by which it may act have proven illusive, multiple and confusing. Data from multiple sources indicate that the toxic species is likely to be a micelle or oligomeric form. Our preliminary data show that only one state of the peptide, the micelle or protofibril form, increases the conductance in planar lipid bilayers and in patch clamped RBL cells. This micellar species also seems to be the physical form actually responsible for the early pathology of the disease. Soluble monomers and fibrils, have no effect, and antibodies specific to the micelle form prevent the conductance increase. The Ab-induced conductance increase takes a particularly interesting and provocative form. Instead of forming channels, amyloid b micelles increase the membrane conductance nonspecifically, probably by thinning the membrane. The same Ab species also increases the conductance induced by the carrier molecule, nonactin, and increases the rate of translocation of the hydrophobic anion tetraphenyl borate as an increase in dielectric constant predicts.

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