Synaptotoxicity of Alzheimer Beta Amyloid Can Be Explained by Its Membrane Perforating Property

Laboratory of Neurophysiology, Department of Physiology, University of Concepción, Concepción, Chile.
PLoS ONE (Impact Factor: 3.23). 07/2010; 5(7):e11820. DOI: 10.1371/journal.pone.0011820
Source: PubMed


The mechanisms that induce Alzheimer's disease (AD) are largely unknown thereby deterring the development of disease-modifying therapies. One working hypothesis of AD is that Abeta excess disrupts membranes causing pore formation leading to alterations in ionic homeostasis. However, it is largely unknown if this also occurs in native brain neuronal membranes. Here we show that similar to other pore forming toxins, Abeta induces perforation of neuronal membranes causing an increase in membrane conductance, intracellular calcium and ethidium bromide influx. These data reveal that the target of Abeta is not another membrane protein, but that Abeta itself is the cellular target thereby explaining the failure of current therapies to interfere with the course of AD. We propose that this novel effect of Abeta could be useful for the discovery of anti AD drugs capable of blocking these "Abeta perforates". In addition, we demonstrate that peptides that block Abeta neurotoxicity also slow or prevent the membrane-perforating action of Abeta.

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Available from: Luis G Aguayo
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    • "This finding led us to propose that the increase in Ca 2+ permeability observed in cells exposed to Aβ results from the activity of calcium ion channels formed by Aβ in the cell surface membrane (Arispe et al. 1994a, b) (Arispe et al. 2010). While there is a growing consensus that Aβ peptides increase membrane conductance by forming conductive pores (Aguayo et al. 2009; Parodi et al. 2010; Sepulveda et al. 2010; Schauerte et al. 2010; Johnson et al. 2011; Tofoleanu and Buchete 2012; DeMuro et al. 2011; Sciacca et al. 2012; Prangkio et al. 2012; Schauerte et al. 2010; DeMuro et al. 2011), there has not been a systematic study on how a "
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    ABSTRACT: Interaction of the Alzheimer's Aβ peptides with the plasma membrane of cells in culture results in chronic increases in cytosolic [Ca(2+)]. Such increases can cause a variety of secondary effects leading to impaired cell growth or cell degeneration. In this investigation, we made a comprehensive study of the changes in cytosolic [Ca(2+)] in single PC12 cells and human neurons stressed by continuous exposure to a medium containing Aβ42 for several days. The differential timing and magnitude of the Aβ42-induced increase in [Ca(2+)] reveal subpopulations of cells with differential sensitivity to Aβ42. These results suggest that the effect produced by Aβ on the level of cytosolic [Ca(2+)] depends on the type of cell being monitored. Moreover, the results obtained of using potent inhibitors of Aβ cation channels such as Zn(2+) and the small peptide NA7 add further proof to the suggestion that the long-term increases in cytosolic [Ca(2+)] in cells stressed by continuous exposure to Aβ is the result of Aβ ion channel activity.
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    • "The interaction of Aβ with cell surface receptors has been repeatedly shown to lead to pathological events, including aberrant cell signalling pathways and the induction of cell death. Although apoptosis is the more common cell death modality observed, necrosis has also been suggested to underlie Aβ neurotoxicity34 owing to the deregulation of intracellular Ca2+ levels which are a consequence of Aβ insertions into the plasma membrane35 and adverse effects on cellular endoplasmic reticula and mitochondria. Therefore, the form of cell death induced upon Aβ treatment was assessed by Annexin-V-7AAD assay and the induction of apoptosis (which accounted for >85% of the cell death) was demonstrated to be both time and concentration dependent (Fig. 3a). "
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    ABSTRACT: Neuronal loss is a major neuropathological hallmark of Alzheimer's disease (AD). The associations between soluble Aβ oligomers and cellular components cause this neurotoxicity. The 37 kDa/67 kDa laminin receptor (LRP/LR) has recently been implicated in Aβ pathogenesis. In this study the mechanism underlying the pathological role of LRP/LR was elucidated. Försters Resonance Energy Transfer (FRET) revealed that LRP/LR and Aβ form a biologically relevant interaction. The ability of LRP/LR to form stable associations with endogenously shed Aβ was confirmed by pull down assays and Aβ-ELISAs. Antibody blockade of this association significantly lowered Aβ42 induced apoptosis. Furthermore, antibody blockade and shRNA mediated downregulation of LRP/LR significantly hampered Aβ42 internalization. These results suggest that LRP/LR is a receptor for Aβ42 internalization, mediating its endocytosis and contributing to the cytotoxicity of the neuropeptide by facilitating intra-cellular Aβ42 accumulation. These findings recommend anti-LRP/LR specific antibodies and shRNAs as potential therapeutic tools for AD treatment.
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    • "Other authors (Jang et al., 2010, 2011; Lin et al., 2001; Quist et al., 2007) proposed that membrane can be damaged due to the creation of ion channels or pores, which induce cell malfunction by an unregulated toxic ion current (Abramov et al., 2011). In summary, the mechanism of Ab toxicity is still not well understood, showing a discrepancy between suggested non-specific membrane alteration (Williams et al., 2011) and ion-channel formation suggested on the base of membrane reconstituted Ab (Jang et al., 2011; Lin et al., 2001), and contradictory nonion channel but membrane perforation alteration mechanisms (Sepulveda et al., 2010). In addition, molecular dynamics simulations by Jang et al. suggested various steps of membrane disorder due to the binding of Ab peptides (Jang et al., 2013). "
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    ABSTRACT: Abstract Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by dementia and memory loss for which no cure or effective prevention is currently available. Neurodegeneration in AD is linked to formation of amyloid plaques found in brain tissues of Alzheimer's patients during post-mortem examination. Amyloid plaques are composed of amyloid fibrils and small oligomers - insoluble protein aggregates. Although amyloid plaques are found on the neuronal cell surfaces, the mechanism of amyloid toxicity is still not well understood. Currently, it is believed that the cytotoxicity is a result of the nonspecific interaction of small soluble amyloid oligomers (rather than longer fibrils) with the plasma membrane. In recent years, nanotechnology has contributed significantly to understanding the structure and function of lipid membranes and to the study of the molecular mechanisms of membrane-associated diseases. We review the current state of research, including applications of the latest nanotechnology approaches, on the interaction of lipid membranes with the amyloid-β (Aβ) peptide in relation to amyloid toxicity. We discuss the interactions of Aβ with model lipid membranes with a focus to demonstrate that composition, charge and phase of the lipid membrane, as well as lipid domains and rafts, affect the binding of Aβ to the membrane and contribute to toxicity. Understanding the role of the lipid membrane in AD at the nanoscale and molecular level will contribute to the understanding of the molecular mechanism of amyloid toxicity and may aid into the development of novel preventive strategies to combat AD.
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