Abstract
The link between metals, Alzheimer's disease (AD) and its implicated protein, amyloid-β (Aβ), is complex and highly studied. AD is believed to occur as a result of the misfolding and aggregation of Aβ. The dyshomeostasis of metal ions and their propensity to interact with Aβ has also been implicated in AD. In this work, we use single molecule atomic force spectroscopy to measure the rupture force required to dissociate two Aβ (1–42) peptides in the presence of copper ions, Cu2+. In addition, we use atomic force microscopy to resolve the aggregation of Aβ formed. Previous research has shown that metal ions decrease the lag time associated with Aβ aggregation. We show that with the addition of copper ions the unbinding force increases notably. This suggests that the reduction of lag time associated with Aβ aggregation occurs on a single molecule level as a result of an increase in binding forces during the very initial interactions between two Aβ peptides. We attribute these results to copper ions acting as a bridge between the two peptide molecules, increasing the stability of the peptide-peptide complex.
Highlights
Amyloid-b (Ab) is a 35–43 long amino acid peptide implicated in the neurodegenerative protein misfolding disease known as Alzheimer’s disease (AD) [1]
We show that when copper ions are added to the Ab force spectroscopy environment, the rupture force increases dramatically, which correlates with a higher rate of aggregation shown by atomic force microscopy (AFM) imaging
The mica slides with adsorbed amyloid were placed in a JPK Nanowizard II atomic force microscope and imaged in air in Intermittent Contact mode using cantilevers purchased from NanosensorsTM (Non-contact/TappingTM mode High resonance frequency; non-coated; tip radius,10 nm)
Summary
Amyloid-b (Ab) is a 35–43 long amino acid peptide implicated in the neurodegenerative protein misfolding disease known as Alzheimer’s disease (AD) [1]. We show that when copper ions are added to the Ab force spectroscopy environment, the rupture force increases dramatically, which correlates with a higher rate of aggregation shown by AFM imaging. This is the first single-molecule study which shows that Cu2+ increases the force of interaction between two single Ab peptides; affecting further aggregation. The mica slides with adsorbed amyloid were placed in a JPK Nanowizard II atomic force microscope and imaged in air in Intermittent Contact mode using cantilevers purchased from NanosensorsTM (Non-contact/TappingTM mode High resonance frequency; non-coated; tip radius ,10 nm). Each experiment was repeated at least twice and at least 3 images for each sample
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