Simple tools untangle Alzheimer’s knot

U. MICHIGAN (US) — Newly-developed molecular tools show promise for “cleansing” the brain of amyloid plaques, implicated in Alzheimer’s disease.

A hallmark of Alzheimer’s disease is the aggregation of protein-like bits known as amyloid-beta peptides into clumps in the brain called plaques that can cause cell death, leading to the disease’s devastating symptoms of memory loss and other mental difficulties.

The mechanisms responsible for the formation of these misfolded proteins and their associations with Alzheimer’s disease are not entirely understood, but scientists believe that copper and zinc ions are somehow involved.

In earlier work, researchers developed dual-purpose molecular tools that both grab metal ions and interact with amyloid-beta.

They went on to show that in solutions with or without living cells, molecules were able to regulate copper-induced amyloid-beta aggregation, not only disrupting the formation of clumps, but also breaking up clumps that already had formed.

“We found that our compound is capable of disassembling the misfolded amyloid clumps to form smaller amyloid pieces, which might be ‘cleansed’ from the brain more easily, demonstrating a therapeutic application of our compound,” says Mi Hee Lim, assistant professor of chemistry at the University of Michigan.

In addition, preliminary tests show that the bi-functional small molecules have a strong potential to cross the blood-brain barrier, the barricade of cells that separates brain tissue from circulating blood, protecting the brain from harmful substances in the bloodstream.

The research is published online in Proceedings of the National Academy of Science.

Building upon that first generation of compounds, Lim and colleagues report a second generation of compounds that are more stable in biological environments. They tested one of those compounds, described in the PNAS paper, in homogenized brain tissue samples from Alzheimer’s disease patients.

“Crossing this barrier is essential for any treatment like this to be successful,” Lim explains.

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