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β-Amyloid (Aβ) is the primary protein component of senile plaques found in Alzheimer's disease. In an aggregated (amyloid fibril, protofibril, or low molecular weight oligomer) state, Aβ has been consistently shown to be toxic to neurons, but the molecular mechanism of this toxicity is poorly understood. We have previously shown that Aβ activates a G_i/o protein, and that inhibition of this specific G protein activation attenuated Aβ-induced cell toxicity. In the present study, we use a kinetic analysis to examine the mechanism of Aβ-induced G protein activation. Using synthetic Aβ(1–40) and phospholipid vesicles containing purified G₀α subunits, we examined the relationship between Aβ concentration, G₀α subunit concentration, GTP concentration and rate of GTP hydrolysis experimentally. We found that at low concentrations of Aβ (less than 10 μM), Aβ increased the rate of GTP hydrolysis over the rate of hydrolysis in …