Neurotoxicity of β-amyloid protein: oligomerization, channel formation, and calcium dyshomeostasis.
Numerous studies have indicated that Alzheimer's amyloid-β protein (Aβ) causes the degeneration of synapses and neurons, finally inducing the pathogenesis of Alzheimer's disease (AD). Recent approaches have emphasized the importance of Aβ oligomerization which enhances its neurotoxicity and synaptotoxicity. Our work as well as other groups' research have demonstrated that Aβ oligomers are directly incorporated into neuronal membranes and form calcium-permeable ion channels (amyloid channels). Although the precise molecular mechanism of Aβ neurotoxicity remains elusive, the formation of amyloid channels and the resultant abnormal elevation of the intracellular calcium levels might be the primary event for neurodegeneration, considering that calcium dyshomeostasis triggers various apoptotic pathways. This article reviews the current understanding of AD pathology based on the hypothesis that the disruption of calcium homeostasis through amyloid channels may be the molecular basis of Aβ neurotoxicity. The potential development of preventive agents for new therapeutic targets is also discussed.
Kawahara
Masahiro
M
Department of Analytical Chemistry School of Pharmaceutical Sciences Kyushu University of Health and Welfare 1714-1 Yoshino-cho, Nobeoka-shi, Miyazaki 882-8508, Japan. kawamasa@phoenix.ac.jp
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000009:adverse effects / Q000378:metabolism; D015220:Calcium Channels / Q000096:biosynthesis*; D006706:Homeostasis; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D018696:Neuroprotective Agents; D002118:Calcium