title: Membrane Incorporation, Channel Formation, and Disruption of Calcium Homeostasis by Alzheimer's β-Amyloid Protein.
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.
authors.affiliation: Department of Analytical Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino-cho, Nobeoka-shi, Miyazaki 882-8508, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawahara
authors.forename: Isao
authors.initials: I
authors.lastname: Ohtsuka
authors.forename: Shoko
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Midori
authors.initials: M
authors.lastname: Kato-Negishi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sadakane