We investigate the role played by membrane composition on the interaction and self-assembly of beta-amyloid peptide (AbetaP1-40) during pore formation in planar lipid membranes (PLMs). Incorporation studies showed that AbetaP does not interact with zwitterionic membranes made up of phosphatidylcholine, whereas the addition of cholesterol or ergosterol to the membranes leads to channel formation. Among the PLMs used, a higher propensity of AbetaP to form channels at low applied potential (+/-20 mV) was observed in 7-dehydrocholesterol and in oxidized cholesterol PLMs. These channels present long lifetimes, high-occurrence frequencies, and are voltage dependent. In particular, the AbetaP channel in oxidized cholesterol showed anion selectivity. Thus cholesterol (and sterols in general) could be considered as targets for AbetaP, which prevents the fibrillation process by increasing incorporation into membranes. Furthermore, by switching the channel selectivity versus anions, cholesterol helps to reduce the imbalance of the cellular ions, calcium included, induced by membrane depolarization, which could be one of the factors responsible for cytotoxicity in Alzheimer's disease.
Cadmium (Cd) is an environmental contaminant, highly toxic to humans. This biologically non-essential element accumulates in the body, especially in the kidney, liver, lung and brain and can induce several toxic effects, depending on the concentration and the exposure time. Cd has been linked to Alzheimer's disease (AD) as a probable risk factor, as it shows higher concentrations in brain tissues of AD patients than in healthy people, its implication in the formation of neurofibrillary tangles and in the aggregation process of amyloid beta peptides (AβPs). AβPs seem to have toxic properties, particularly in their aggregated state; insoluble AβP forms, such as small and large aggregates, protofibrils and fibrils, appear to be implicated in the pathogenesis of AD. In our study, we have evaluated the effect of Cd, at different concentrations, both on the AβP1-42 ion channel incorporated in a planar lipid membrane made up of phosphatidylcholine containing 30 % cholesterol and on the secondary structure of AβP1-42 in aqueous environment. Cadmium is able to interact with the AβP1-42 peptide by acting on the channel incorporated into the membrane as well as on the peptide in solution, both decreasing AβP1-42 channel frequency and in solution forming large and amorphous aggregates prone to precipitate. These experimental observations suggesting a toxic role for Cd strengthen the hypothesis that Cd may interact directly with AβPs and may be a risk factor in AD.
Kissper is a 39-residue peptide isolated from kiwi fruit (Actinidia deliciosa). Its primary structure, elucidated by direct protein sequencing, is identical to the N-terminal region of kiwellin, a recently reported kiwi fruit allergenic protein, suggesting that kissper derives from the in vivo processing of kiwellin. The peptide does not show high sequence identity with any other polypeptide of known function. However, it displays a pattern of cysteines similar, but not identical, to those observed in some plant and animal proteins, including toxins involved in defence mechanisms. A number of these proteins are also active on mammalian cells. Functional characterization of kissper showed pH-dependent and voltage-gated pore-forming activity, together with anion selectivity and channeling in model synthetic PLMs, made up of POPC and of DOPS:DOPE:POPC. A 2DNMR analysis indicates that in aqueous solution kissper has only short regions of regular secondary structure, without any evident similarity with other bioactive peptides. Comparative analysis of the structural and functional features suggests that kissper is a member of a new class of pore-forming peptides with potential effects on human health.
Mercury (Hg) and lead (Pb) are known to be toxic non-radioactive elements, with a well-described neurotoxicology.Much evidence supports the implication of metals as potential risk cofactors in Alzheimer's disease (AD). Although the action mechanism of the two metals remains unclear, Hg and Pb toxicity in AD could depend on their ability to favour misfolding and aggregation of amyloid beta proteins (As) that seem to have toxic properties, particularly in their aggregated state. In our study, we evaluated the effect of Hg and Pb both on the Aβ42 ion channel incorporated in a planar lipid membrane made up of phosphatidylcholine containing 30% cholesterol and on the secondary structure of Aβ42 in aqueous environment. The effects of Hg and Pb on the A42 peptide, observed on the channel incorporated into the membrane as well as on the peptide in solution, both decreasing A42 channel frequency and in solution forming large and amorphous aggregates that are prone to precipitate, are dependent on metal concentration. These experimental data suggest that Hg and Pb interact directly with As, strengthening the hypothesis that the two metals may be a risk factor in AD.
Human Calcitonin (hCt) is a peptide hormone which has a regulatory action in calcium-phosphorus metabolism. It is currently used as a therapeutic tool in bone pathologies such as osteoporosis and Paget's disease. However, due to its amphiphilic property tends to form a gelatinous solution in water which consists of fibrils that limits its therapeutic use. Here we show that sodium dodecyl sulfate (SDS), an anionic detergent able to induce and stabilize alpha-helices in polypeptides, at a monomeric concentration ranging between 0.26 mM-5 pM (all concentrations are below the CMC), increases the rate and number of hCt channel formation in planar lipid membranes, at both high and low hCt concentrations, with a maximum increase at a molecular hCt/SDS ratio of 1000:1. This effect could be interpreted as a counteraction to the fibrillation process of hCt molecules by removing molecules available for aggregation from the fluid; furthermore, this action, independently of channel formation in the cell membrane, could improve the peptide-receptor interaction. The action of SDS could be attributable to the strength of the sulfate negative charge and the hydrophobic chain; in fact, a similar effect was obtained with lauryl sarcosine and not with a neutral detergent such as n-dodecyl-beta-D-maltoside. The very low molecular ratio between SDS and peptide is suggestive of a possible catalytic action of SDS that could induce alpha-helices, the appropriate structures for interacting with the membrane. Moreover, in the experimental conditions investigated, the addition of SDS does not modify the membrane's electrical properties and most of the channel properties. This finding may contribute to the knowledge of environment-folding diseases due to protein and peptides.
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