Abstract
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 Aβ 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, Aβ induces perforation of neuronal membranes causing an increase in membrane conductance, intracellular calcium and ethidium bromide influx. These data reveal that the target of Aβ is not another membrane protein, but that Aβ 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 Aβ could be useful for the discovery of anti AD drugs capable of blocking these “Aβ perforates”. In addition, we demonstrate that peptides that block Aβ neurotoxicity also slow or prevent the membrane-perforating action of Aβ.
Highlights
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative brain disorder that leads to major debilitating cognitive deficits in the elderly
The working hypothesis of AD is that excess of Ab either i) binds to membrane receptors affecting their functions [5], ii) interferes with signaling cascades [6,7,8] or iii) directly disrupts neuronal membranes causing pore formation leading to alterations in ionic homeostasis [9]
The traces in figure 1B clearly show that the amplitude and time course of the capacitive current increased with time and this was similar to that induced by gramicidin (Fig. 1C)
Summary
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative brain disorder that leads to major debilitating cognitive deficits in the elderly. The working hypothesis of AD is that excess of Ab either i) binds to membrane receptors affecting their functions [5], ii) interferes with signaling cascades [6,7,8] or iii) directly disrupts neuronal membranes causing pore formation leading to alterations in ionic homeostasis [9]. The latter is an attractive hypothesis because it could explain several effects of Ab in brain neurons, it is largely unknown if this can occur in native brain neuronal membranes. In agreement with this idea, atomic force microscopy (AFM) in lipid environments and molecular dynamic analysis have shown the presence of molecular entities with inner diameters in the 1.5–2.6 nm range [10,11] which were similar to those generated by other peptidergic molecules known to form pores in cell membranes, such as amylin and a-synuclein [12]
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