Disruption of calcium homeostasis in the pathogenesis of Alzheimer's disease and other conformational diseases.

Conformational changes of Alzheimer's beta-amyloid protein (AbetaP) enhance its neurotoxicity and play important roles in the pathogenesis of Alzheimer's disease. Recent studies have suggested that a common mechanism is based on diverse "conformational diseases". They share similarity in their formation of beta-sheet containing amyloid fibrils by disease-related proteins and the introduction of apoptotic degeneration. Numerous studies, including our own, have revealed that AbetaP and several disease-related proteins are capable of directly incorporating into membranes, forming calcium-permeable ion channels, and causing abnormal elevation of intracellular calcium levels. This article reviews the current understanding of the pathology of conformational diseases based on the hypothesis that the disruption of calcium homeostasis through amyloid channels may form the molecular basis of neurotoxicity of AbetaP and other disease-related proteins. The roles of membrane lipids and potential development of preventive agents are also discussed.