Aβ ion channels.: Prospects for treating Alzheimer's disease with Aβ channel blockers

The main pathological features in the Alzheimer's brain are progressive depositions of amyloid protein plaques among nerve cells, and neurofibrillary tangles within the nerve cells. The major components of plaques are A beta peptides. Numerous reports have provided evidence that A[ peptides are cytotoxic and may play a role in the pathogenesis of AD. An increasing number of research reports support the concept that the A beta-membrane interaction event may be followed by the insertion of A beta into the membrane in a structural configuration which forms an ion channel. This review summarizes experimental procedures which have been designed to test the hypothesis that the interaction of A beta with a variety of membranes, both artificial and natural, results in the subsequent formation of A beta ion channels We describe experiments, by ourselves and others, that support the view that A beta is cytotoxic largely due to the action of A beta channels in the cell membrane. The interaction of A beta with the surface of the cell membrane may results in the activation of a chain of processes that, when large enough, become cytotoxic and induce cell death by apoptosis. Remarkably, the blockage of A beta ion channels at the surface of the cell absolutely prevents the activation of these processes at different intracellular levels, thereby preserving the life of the cells. As a prospect for therapy for Alzheimer's disease, our findings at cellular level may be testable on AD animal models to elucidate the potential role and the magnitude of the contribution of the A channels for induction of the disease. Published by Elsevier B.V.