Metal-based molecule inhibits the development of Alzheimer’s peptides

Alzheimer, a common form of dementia, affecting approximately 50 million people worldwide. With time, Alzheimer’s Patients develop severe memory impairment and lose the ability to carry out everyday tasks.

One of the key hallmarks of Alzheimer’s disease is the accumulation of the amyloid-β (Aβ) peptide in the brain.

Recently, Imperial scientists have created a metal-based molecule that inhibits built up of the peptide amyloid-β. Using ultrasound, it was found that this newly created molecule can cross the blood-brain barrier in mice, targeting the part of the brain where the damaging peptide most often accumulates.

The metal-based molecule was found to be highly effective at preventing the build-up of amyloid-β in lab-based studies. It is also non-toxic to human brain-like cells, and that it can cross the blood-brain barrier in mice with the help of a technique using microbubbles and focused ultrasound.

First author Tiffany Chan, from the Departments of Chemistry and Bioengineering at Imperial, said: “Very few metal-based molecules have been investigated as potential inhibitors of amyloid-β build-up because of toxicity issues and difficulty crossing the blood-brain barrier.”

“The molecule we have designed can interfere with amyloid-β and seems non-toxic, and it can be delivered across the blood-brain barrier using ultrasound, which means you don’t need an invasive procedure.”

LA-ICP-MS (Laser Ablation Inductively Coupled Plasma Mass Spectrometry) image of the brain highlighting the area where one of the metal complexes under study accumulates. This area (left hippocampus) was sonicated; no evidence of metal complex accumulation can be seen in the right hippocampus (no-ultrasound control)

The molecule is centered around the metal cobalt, surrounded by organic molecules atoms that form a complex, which ties to amyloid-β peptides, restricting them from binding each other and developing. The particle additionally incorporates chemical groups that prevent it from being taken up into human nerve cells, reducing its toxicity.

Using a technique, scientists determined if the molecule could cross the BBB. The method involves injecting the molecule alongside microbubbles into the veins of mice.

When ultrasound is directed at the brain, the microbubbles rapidly move to and fro, opening the BBB and allowing the molecule to enter the brain in a non-invasive and targeted way.

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

Co-author Professor Ramon Vilar from the Department of Chemistry at Imperial said, “This study shows the potential that metal-based molecules have in preventing amyloid-β aggregation. The new compound will be studied in more depth to establish whether it can also prevent amyloid-β build-up in mice without having unwanted toxic side effects.”

Journal Reference:

1. Tiffany G. Chan et al. Modulation of amyloid-β aggregation by metal complexes with a dual binding mode and their delivery across the blood-brain barrier using focused ultrasound. DOI: 10.1039/D1SC02273C

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