Calcium dyshomeostasis and neurotoxicity of Alzheimer's beta-amyloid protein

Neurotoxicity of Alzheimer's beta-amyloid protein (A beta P) is central to the pathogenesis of Alzheimer's disease (AD). Recent approaches have emphasized the importance of A beta P oligomerization, which causes synaptic degeneration and neuronal loss, finally leading to the pathogenesis of AD. Although the precise molecular mechanism of A beta P neurotoxicity remains elusive, our and other numerous findings have demonstrated that A beta P directly incorporated into neuronal membranes formed calcium-permeable ion channels (amyloid channels) and resulted in an abnormal elevation of the intracellular calcium levels. The formation of amyloid channels and the abnormal increase of intracellular Ca2+ have also been commonly observed in other neurodegenerative diseases, including conformational diseases such as prion disease or dementia with Lewy bodies. This article reviews the current understanding of the pathology of AD based on the hypothesis that the disruption of calcium homeostasis through amyloid channels may be the molecular basis of A beta P neurotoxicity. The potential development of preventive agents is also discussed.