Targeting Alzheimer’s hallmarks – a metal complex that limits plaque formation and free radical toxicity

June 18, 2019
Figure: Key interactions of the antioxidant compound FeL1 with copper-containing Amyloid-beta peptide (Aβ-Cu). Left: The amyloid-beta peptide shown in complex with copper (key amino acid residues drawn in red; Cull drawn in blue). The Cu-containing peptide can cause the production of tissue-damaging free radicals (ROS: reactive oxygen species) from stable oxygen molecules in the tissue. However, when the copper-containing peptide is in the presence of the iron (Fe)-containing compound FeL1 (right: FeL1-Aβ-Cu; FeL1 shown bound to the peptide, with the Fe drawn in green), the conversion of oxygen to free radicals (ROS) is reduced.

The motivation – Dementia affects about 50 million people worldwide, with Alzheimer’s being the most well-known of the neurodegenerative diseases. One of the main hallmarks of Alzheimer’s Disease (AD) are insoluble amyloid plaques that form in the brain due to the deposition of a small protein known as amyloid-β (Aβ) peptide. This peptide can interact with copper (Cu) ions, and high levels of copper are found in amyloid plaques. Researchers suspect that the Cu-containing plaques generate a highly reactive molecular species known as free radicals that damage the brain tissue and are a major contributor to brain toxicity. To begin testing this idea, the group of Dr. Tim Storr, in collaboration with Drs. Charles Walsby and Michael Silverman (Simon Fraser University) and Dr. Zeev Gross (Technion-Israel Institute of Technology, Israel) initiated a study on the effect of the iron-containing antioxidant compound FeL1 on the aggregation of Aβ peptides and the Cu-induced generation of free radicals by these plaques.  

The discovery – The tests conducted by this research team revealed that FeL1 interacts strongly with the Aβ peptide and restricts peptide aggregation. Furthermore, this iron-containing compound binds to the peptide in the presence of copper and limits the generation of tissue-damaging free radicals. These results lay the groundwork for exploring the development of compounds such as FeL1 that act on multiple targets for Alzheimer’s disease therapy.

Its significance – There is a lack of effective drugs to treat Alzheimer’s Disease, with currently approved therapies only useful in the early stages of the disease. The number of people affected by dementia is expected to increase significantly over the next 25 years, and thus the need to identify new therapies is critical. The current findings suggest that the design of drugs that operate on multiple targets, such as peptide aggregation and free radical toxicity, is promising, and the Fe compound studied provides a starting point for further design improvements. 

Read the paper – “A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation” byGomes, LMF; Mahammed, A; Prosser, KE; Smith, JR; Silverman, MAWalsby, CJ; Gross, Z; Storr, TChemical Science 10(6): 1634-1643 (2019). DOI: 10.1039/c8sc04660c.

Website article compiled by Jacqueline Watson with Theresa Kitos