Abstract

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.

Highlights

  • Alzheimer’s disease (AD) is a severe type of senile dementia, affecting a large portion of elderly people worldwide

  • The precise cause of AD remains elusive, it is widely accepted that oligomerization of Alzheimer’s β-amyloid protein atomic force microscopy (AFM) (AβP) and the consequent neurodegeneration might be the cause of neuronal death in AD patients [2, 3]

  • We focus on the “amyloid channel hypothesis”—direct insertion into membranes of AβP, formation of channels, and disruption of calcium homeostasis via unregulated cytotoxic channels may be the molecular basis of its neurotoxicity [8,9,10]

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Summary

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. 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. The possible development of new drugs by influencing membrane lipid properties and attenuating amyloid channels for the treatment and prevention of AD is discussed

Conformational Changes of AβP and Its Neurotoxicity
AβP-Induced Neurotoxicity and the Disruption of Calcium Homeostasis
Channel Formation by AβP
Disruption of Calcium Homeostasis
Role of Membrane Lipids in the Formation of Amyloid Channels
Possible Candidate for the Treatment of AD
Amyloid Channel Hypothesis
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