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Study Leads to Alzheimer's Breakthrough

Published: Thursday, October 10, 2013
Last Updated: Thursday, October 10, 2013
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Researchers at the Medical Research Council Toxicology Unit have used an orally-administered compound to block a major pathway leading to brain cell death in mice, preventing neurodegeneration.

The team had found previously that the build up of misfolded proteins in the brains of mice with prion disease over-activates a natural defence mechanism in cells, which switches off the production of new proteins. This mechanism would normally switch back ‘on’ again, but in these mice the continued build-up of misshapen protein keeps the switch turned ‘off’. This is the trigger point leading to brain cell death, as the key proteins essential for nerve cell survival stop being made. 

Originally, the team injected a protein that blocked the ‘off’ switch of the pathway into a small region of the brain, and by doing this were able to restore protein production, and halt the neurodegeneration. The brain cells were protected, and protein levels and synaptic transmission (the way in which brain cells signal to each other) were restored allowing the mice to live longer. This led the scientists to predict that compounds able to block this pathway would also protect brain cells.

In the new study, published in Science Translational Medicine, the researchers gave by mouth a drug-like compound against the pathway to prion infected mice, hoping to block the off-switch in the same way.  The compound, which had originally been developed by GlaxoSmithKline for a different purpose, was able to enter the brain from the bloodstream and halt the disease, throughout the whole brain. However, this compound, despite protecting the brain, also produced weight loss in the mice and mild diabetes, due to damage to the pancreas.*

The researchers studied mice with prion disease because these mouse models currently provide the best animal representation of human neurodegenerative disorders in which the build up of misshapen proteins is linked with brain cell death.  These include Alzheimer’s and Parkinson’s as well as prion diseases.  Another paper in Nature Neuroscience last month highlighted this pathway as a potential therapeutic target in treating Alzheimer’s.

Professor Giovanna Mallucci, who led the team, said, “Our previous study predicted that this pathway could be a target for treatment to protect brain cells in neurodegenerative disease.  So we administered a compound that blocks it to mice with prion disease. We were extremely excited when we saw the treatment stop the disease in its tracks and protect brain cells, restoring some normal behaviours and preventing memory loss in the mice.

“We’re still a long way from a usable drug for humans – this compound had serious side effects. But the fact that we have established that this pathway can be manipulated to protect against brain cell loss first with genetic tools and now with a compound, means that developing drug treatments targeting this pathway for prion and other neurodegenerative diseases is now a real possibility.”

Professor Hugh Perry, chair of the Medical Research Council's Neuroscience and Mental Health Board, said, “Misshapen proteins in prion diseases and other human neurodegenerative disorders, such as Alzheimer’s and Parkinson’s, also over-activate this fundamental pathway controlling protein synthesis in the brains of patients. Despite the toxicity of the compound used, this study indicates that, in mice at least, we now have proof-of-principle of a therapeutic pathway that can be targeted. This might eventually aid the development of drugs to treat people suffering from dementias and other devastating neurodegenerative diseases.”


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