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May 21, 2013

"Catalytic Trigger" for Alzheimer’s Identified

  • Scientists at the University of Cambridge have identified what they’ve dubbed a “catalytic trigger” for the onset of Alzheimer’s disease—the moment at which key proteins become aberrant, causing a chain reaction that leads to neuronal death in the brain.

    Writing today in the Proceedings of the National Academy of Sciences, Cambridge Professor Christopher Dobson, Ph.D., and his colleagues describe the underlying nature of how such proteins go wrong, leading to the eventual buildup of amyloid fibrils.

    “We’ve now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed,” Dr. Dobson said in a statement. “This is the key pathway to detect, target, and intervene—the molecular catalyst that underlies the pathology.”

    Using kinetic experiments and equations, the researchers found that a secondary nucleation process generates these toxic oligomers, which are initially clusters consisting of just a few protein molecules. Small and highly diffusible, these complexes navigate around brain cells, forming larger protein deposits (or plaques), killing neurons and causing memory loss and other symptoms of dementia along the way.

    The Cambridge team is hopeful these new molecular insights might inform diagnostic and drug development for dementia-related diseases.

    “There are no disease-modifying therapies for Alzheimer’s and dementia at the moment, only limited treatment for symptoms. We have to solve what happens at the molecular level before we can progress and have real impact,” Cambridge’s Tuomas Knowles, Ph.D., study co-author, said in a statement. “We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to ‘recreate the crime scene’ at the molecular root of Alzheimer’s disease.”

    He added: “With a disease like Alzheimer’s, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we’ve found how the oligomers are created, we know what process we need to turn off.”

    The study, “Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism,” appeared online in PNAS May 20.



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