MEMBRANE CURRENTS INDUCED IN XENOPUS OOCYTES BY THE C-TERMINAL FRAGMENT OF THE BETA-AMYLOID PRECURSOR PROTEIN

There is mounting evidence that at least some of the neurotoxicity ass ociated with Alzheimer's disease (AD) is due to proteolytic fragments of the beta-amyloid precursor protein (beta APP). Most research has fo cused on the amyloid beta protein (A beta), which has been shown to po ssess ion channel activity. However, the possible role of other cleave d products of the beta APP is less clear. We have investigated the abi lity of various products of beta APP to induce membrane ion currents b y applying them to Xenopus oocytes, a model system used extensively fo r investigating electrophysiological aspects of cellular, including ne uronal, signalling. We focussed on the 105-amino-acid C-terminal fragm ent (CT105) (containing the full sequence A beta), which has previousl y been found to be toxic to cells, although little is known about its mode of action. We have found that CT105 is exceedingly potent, with a threshold concentration of 100-200 nM, in inducing nonselective ion c urrents when applied from either outside or inside the oocyte and is m ore effective than either beta APP or the A beta fragments, beta(25-35 ) or beta(1-40). The ion channel activity of CT105 was concentration d ependent and blocked by a monoclonal antibody to A beta. These results suggest the possible involvement of CT105 in inducing the neural toxi city characteristic of AD.