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.

Disruption of Calcium Homeostasis in Alzheimer’s Disease: Role of Channel Formation by β Amyloid Protein

“…The effect of AβP was similar to that of gramicidin and amphotericin which are commonly used to perforate neuron membranes. Furthermore, we have revealed that AβP directly caused the disruption of liposomal membrane vesicles by observing the release of fluorescent dye (Kawahara et al, 2011b). These results are consistent with the findings that AßP causes membrane disruption, increases membrane permeability, causes hemolysis, and changes membrane fluidity (Eckert et al, 2005).…”

“…The conformational diseases includes prion diseases, triplet-repeat diseases, e.g., Huntington's disease, Parkinson's disease and other neurodegenerative diseases that can be categorized under dementia with Lewy bodies (DLB). Increasing evidence indicates that most of these disease-related amyloidogenic proteins or their peptide fragments are directly incorporated into membranes to form ion channels as well as AβP (Lashuel and Lansbury, 2002;Kawahara et al, 2011b). It was also demonstrated that AßP (1-40), α-synuclein, amylin, ABri, or other amyloidogenic peptides morphologically similar common ion channel-like structures and elicit single channel currents using AFM, CD, gel electrophoresis, and electrophysiological recordings (Quist et al, 2005;Lal et al, 2007).…”

“…Here, we focus on the 'amyloid channel hypothesis' Lin et al 2001;Kawahara, 2011b), namely, that the direct incorporation of AβPs and the subsequent imbalances of Ca 2+ and other ions through amyloid channels may be the primary event in AßP neurotoxicity. In this chapter, we review the current understanding of the link between Ca 2+ homeostasis and AD pathogenesis based on the amyloid channel hypothesis the characteristics of AβP-induced neurotoxicity and synaptotoxicity caused by Ca 2+ dyshomeostasis via amyloid channels.…”

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

“…Oligomer cytotoxicity appears to result from the aberrant interactions of such species with the lipid bilayers, disrupting cell membranes and impairing their ability to maintain cellular homeostasis [14][15][16][17][18]. Several studies support the notion that membrane disruption induced by A␤ allows the entry of small molecules and ions, mainly free Ca 2+ ions [19][20][21][22]. In particular, it was reported that A␤ can induce a generalized thinning of the phospholipid bilayer, thereby resulting in perturbation of Ca 2+ fluxes [23].…”

The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

“…A common hypothesis used to explain the toxicity induced by A␤ is the formation of amyloid pores in the plasma membrane. Regarding this, several studies from our and other laboratories support the notion that membrane disruptions are induced by A␤ [6][7][8][9][10][11][12][13]. Furthermore, A␤ perforation allows the entry of small molecules and ions, such as calcium, into the cells [6,7,12].…”