Metal-based molecules show promise against accumulation of Alzheimer’s peptides

In lab tests, Imperial Oil researchers created a metal-based molecule that inhibits the build-up of a peptide associated with Alzheimer’s disease.

A peptide is a fragment of a protein, and one of the main characteristics of Alzheimer’s disease is the accumulation of a specific peptide called amyloid-β. The team demonstrated that using ultrasound, their molecule can cross the blood-brain barrier in mice, targeting the part of the brain where the harmful peptide most often accumulates.

Alzheimer’s disease is the most common form of dementia, affecting approximately 50 million people worldwide. There is an urgent need to develop drugs capable of preventing or reversing the effects of this devastating disease.

Some metal-based molecules have previously been designed to prevent the build-up of amyloid-β. However, these are often toxic to cells or are unable to cross the blood-brain barrier (BBB) ​​- a semi-permeable protective barrier that carefully regulates the passage of substances entering and leaving the brain.

Today, a team from the Departments of Chemistry and Bioengineering at Imperial College London has designed a metal-based molecule that is highly effective in preventing the build-up of amyloid-β in laboratory studies.

They also showed that the molecule is not toxic to human brain-like cells and that it can cross the blood-brain barrier in mice using a technique using microbubbles and focused ultrasound. The results are published in the journal Chemical sciences.

First author Tiffany Chan, of Imperial Oil’s chemistry and bioengineering departments, said: “Very few metal-based molecules have been studied as potential inhibitors of amyloid-β accumulation due to toxicity problems and difficulty crossing the blood-brain barrier. The molecule we designed is able to interfere with amyloid-β and appears to be non-toxic, and it can be delivered across the blood-brain barrier using ultrasound, which means you don’t have to no need for an invasive procedure. “

The molecule is centered around the metallic cobalt, surrounded by organic molecules that form a complex, which binds to amyloid-β peptides, preventing them from binding to each other and accumulating. The molecule also incorporates chemical groups that prevent it from being absorbed by human nerve cells, thereby reducing its toxicity.

To demonstrate that the molecule could cross the BBB, the team used a technique that involves injecting the molecule with microbubbles into the veins of mice. When the ultrasound is directed to the brain, the microbubbles move back and forth rapidly, opening up the BBB and allowing the molecule to enter the brain in a non-invasive and targeted manner.

The team was able to focus the ultrasound on the hippocampus region of the brain, which is often strongly impacted by the accumulation of amyloid-β in the early stages of Alzheimer’s disease. They were also able to show how specific ultrasound targeting can be by delivering the molecule only to the left hippocampus.

The molecule was found to be well tolerated by mice, which showed no adverse effects after several weeks. Co-author Professor Ramon Vilar, Department of Chemistry at Imperial, said: “This study shows the potential of metal-based molecules to prevent aggregation of amyloid-β. The new compound will be studied further to determine if it can also prevent amyloid build-up in mice without having unwanted toxic side effects. ”

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