Amyloid Peptide Channels

Kagan, Bruce L.; Azimov, Rustam; Azimova, Rushana

doi:10.1007/s00232-004-0709-4

Cited by 165 publications

(162 citation statements)

References 83 publications

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“…It is widely accepted that, at least in most cases, cell degeneration in amyloid diseases is mediated by a toxic mechanism involving the interaction of the aggregated species with the plasma membrane of the affected cells (Kagan et al, 2004). Some authors suggest that, by affecting plasma membrane fluidity, cholesterol content affects the incorporation of toxic aggregates into the plasma membrane itself (Arispe and Doh, 2002).…”

Section: Discussionmentioning

confidence: 99%

Insights into the molecular basis of the differing susceptibility of varying cell types to the toxicity of amyloid aggregates

Cecchi

Baglioni²,

Fiorillo³

et al. 2005

Journal of Cell Science

110

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It has been reported that different tissue or cultured cell types are variously affected by the exposure to toxic protein aggregates, however a substantial lack of information exists about the biochemical basis of cell resistance or susceptibility to the aggregates. We investigated the extent of the cytotoxic effects elicited by supplementing the media of a panel of cultured cell lines with aggregates of HypF-N, a prokaryotic domain not associated with any amyloid disease. The cell types exposed to early, pre-fibrillar aggregates (not mature fibrils) displayed variable susceptibility to damage and to apoptotic death with a significant inverse relation to membrane content in cholesterol. Susceptibility to damage by the aggregates was also found to be significantly related to the ability of cells to counteract early modifications of the intracellular free Ca2+ and redox status. Accordingly, cell resistance appeared related to the efficiency of the biochemical equipment leading any cell line to sustain the activity of Ca2+ pumps while maintaining under control the oxidative stress associated with the increased metabolic rate. Our data depict membrane destabilization and the subsequent early derangement of ion balance and intracellular redox status as key events in targeting exposed cells to apoptotic death.

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Section: Discussionmentioning

confidence: 99%

Insights into the molecular basis of the differing susceptibility of varying cell types to the toxicity of amyloid aggregates

Cecchi

Baglioni²,

Fiorillo³

et al. 2005

Journal of Cell Science

110

View full text Add to dashboard Cite

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“…Micro-circumstances on the membranes, such as the presence of rafts, may influence this process [56]. These data and other reports culminated in what came to be known as the "channel hypothesis", implicating amyloid peptide channels in the pathogenic ion dysregulation observed in degenerative disease [57,58]. In this respect, A␤ may share this mechanism of toxicity with the similar mechanism underlying the toxicity of various antimicrobial or antifungal peptides, such as alamethicin, gramicidin, magainin 2, and melittin, which also exhibit channel forming ability and cell toxicity [59].…”

Section: Cellular Membrane and A␤ Oligomers Toxicitymentioning

confidence: 92%

Molecular Mechanisms of Amyloid Oligomers Toxicity

Kayed

Lasagna‐Reeves

2012

JAD

323

283

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Abstract. Amyloid oligomers have emerged as the most toxic species of amyloid-␤ (A␤). This hypothesis might explain the lack of correlation between amyloid plaques and memory impairment or cellular dysfunction. However, despite the numerous published research articles supporting the critical role A␤ oligomers in synaptic dysfunction and cell death, the exact definition and mechanism of amyloid oligomers formation and toxicity still elusive. Here we review the evidence supporting the many molecular mechanisms proposed for amyloid oligomers toxicity and suggest that the complexity and dynamic nature of amyloid oligomers may be responsible for the discrepancy among these mechanisms and the proposed cellular targets for amyloid oligomers.

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“…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 formation of stable pores and ion channels, usually defined "annular protofibrils", in the cell membrane has also been proposed for amyloid-induced toxicity, in analogy to prokaryotic pore-forming toxins [24][25][26], although more recent data have not supported this hypothesis. Finally, a mechanism of A␤ oligomer interaction with cell membranes involving specific binding to endogenous calcium-permeable channels has also been suggested [18].…”

Section: Introductionmentioning

confidence: 99%

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

Cascella

Evangelisti

Bigi

et al. 2017

JAD

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Abstract. An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-␤ peptide (A␤ 42 ), with intracellular flux of Ca 2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca 2+ ions induced by A␤ 42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by A␤ 42 oligomers with low solvent-exposed hydrophobicity (A−) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca 2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.

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Amyloid Peptide Channels

Cited by 165 publications

References 83 publications

Insights into the molecular basis of the differing susceptibility of varying cell types to the toxicity of amyloid aggregates

Insights into the molecular basis of the differing susceptibility of varying cell types to the toxicity of amyloid aggregates

Molecular Mechanisms of Amyloid Oligomers Toxicity

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

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