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Membrane Incorporation, Channel Formation, and Disruption of Calcium Homeostasis by Alzheimer's β-Amyloid Protein

DOI: 10.4061/2011/304583

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Oligomerization, conformational changes, and the consequent neurodegeneration of Alzheimer's β-amyloid protein (AβP) play crucial roles in the pathogenesis of Alzheimer's disease (AD). Mounting evidence suggests that oligomeric AβPs cause the disruption of calcium homeostasis, eventually leading to neuronal death. We have demonstrated that oligomeric AβPs directly incorporate into neuronal membranes, form cation-sensitive ion channels (“amyloid channels”), and cause the disruption of calcium homeostasis via the amyloid channels. Other disease-related amyloidogenic proteins, such as prion protein in prion diseases or α-synuclein in dementia with Lewy bodies, exhibit similarities in the incorporation into membranes and the formation of calcium-permeable channels. Here, based on our experimental results and those of numerous other studies, we review the current understanding of the direct binding of AβP into membrane surfaces and the formation of calcium-permeable channels. The implication of composition of membrane lipids and the possible development of new drugs by influencing membrane properties and attenuating amyloid channels for the treatment and prevention of AD is also discussed. 1. Introduction Alzheimer’s disease (AD) is a severe type of senile dementia, affecting a large portion of elderly people worldwide. It is characterized by profound memory loss and inability to form new memories. The pathological hallmarks of AD are the presence of numerous extracellular deposits, termed senile plaques, and intraneuronal neurofibrillary tangles (NFTs). The degeneration of synapses and neurons in the hippocampus or cerebral cortex is also observed [1]. The major components of NFTs are phosphorylated tau proteins, and that of senile plaques are β-amyloid proteins (AβPs). Although the precise cause of AD remains elusive, it is widely accepted that oligomerization of AβP and the consequent neurodegeneration might be the cause of neuronal death in AD patients [2, 3]. There is considerable interest regarding the mechanism by which AβPs cause neurodegeneration. AβPs have been reported to cause various adverse effects on neuronal survivals, such as the production of reactive oxygen species, the induction of cytokines, the induction of endoplasmic reticulum (ER) stresses, and the abnormal increase in intracellular calcium levels ([Ca2+]i) [4]. These adverse effects are complex and may be interwoven. Of these effects, the disruption of calcium homeostasis could be the earliest and primary event, since Ca2+ ions are essential for various neuronal functions. The


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