The amyloid-β peptide is one of the hallmarks of Alzheimer's disease, forming senile-plaques around neurons and leading to neurodegeneration and brain shrinkage. The identification of these binding sites could be crucial for developing novel therapies to target Alzheimer's disease. As up until now drugs have failed to remove the senile plaques that surround neurons, a new target on the peptide may be the key to removing the toxic build-up.

Footprint on the fibril

The group used the photophysical and photochemical properties of a rhenium-based complex to identify the binding site. This rhenium complex lights up brightly under UV light when bound to amyloid-β peptide, where it also triggers oxidation on the site. The oxidation "footprint" is hence revealed through tandem mass spectrometry by identifying the exact binding site where the rhenium complex and peptide connect.

The senile plaques observed are formed of aggregated and misfolded amyloid-β peptide fibrils. The binding site revealed from this study is present due to these plaques, exposing a hydrophobic region where the rhenium complex binds to the misfolded fibril.

Drug binding target

The author, Angel Martí, suggests that the hydrophobic binding site is common to multiple molecules, and therefore has potential to become a therapeutic target. The development of molecules that bind to the site and inhibit amyloid-β peptide aggregation into toxic plaques could provide a treatment option for Alzheimer's disease patients.

Martí's research team collaborated with a computational biochemistry group at the University of Miami that used computer simulations to test various binding sites to the amyloid-β peptide fibrils. This allowed for predictive testing of where the probe would be able to bind, before attempting the process with the physical probe.

Photochemical future

The photochemical techniques used in this paper are not uncommon in nature. For example, the biosynthesis of vitamin D relies heavily on photochemical reactions. The use of light-induced reactions in this study may present the opportunity for similar tests in other protein misfolding diseases, or even establish novel binding sites on other Alzheimer's disease-related proteins.

The group has even proposed that by altering the complex to absorb red light – which can penetrate through tissues – the technique could be employed in living animal models, and potentially be used on humans one day. Cutting-edge techniques like this could reinvigorate the drug discovery pipeline for non-treatable conditions such as Alzheimer's disease, by identifying new binding sites for researchers to therapeutically target.