Abeta ion channels. Prospects for treating Alzheimer's disease with Abeta 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 Abeta peptides. Numerous reports have provided evidence that Abeta peptides are cytotoxic and may play a role in the pathogenesis of AD. An increasing number of research reports support the concept that the Abeta-membrane interaction event may be followed by the insertion of Abeta 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 Abeta with a variety of membranes, both artificial and natural, results in the subsequent formation of Abeta ion channels We describe experiments, by ourselves and others, that support the view that Abeta is cytotoxic largely due to the action of Abeta channels in the cell membrane. The interaction of Abeta 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 Abeta 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 Abeta channels for induction of the disease.
Arispe
Nelson
N
Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services University School of Medicine, USUHS, 4301 Jones Bridge Rd. Bethesda, MD 20814, USA. narispe@usuhs.mil
Diaz
Juan C
JC
Simakova
Olga
O
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D003603:Cytotoxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000378:metabolism / Q000627:therapeutic use*; D008567:Membranes, Artificial
D016229:Amyloid beta-Peptides; D003603:Cytotoxins; D007473:Ion Channels; D049990:Membrane Transport Modulators; D008567:Membranes, Artificial