New compound halts Alzheimer's in mice

10 October 2013

Researchers at the University of Leicester have discovered an oral treatment that blocks the process causing brain cell death in neurodegenerative diseases such as Alhzheimer's.

The same team had previously identified a major pathway leading to brain cell death. They found 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 essential for cell survival. They highlighted this pathway as a potential therapeutic target in treating Alzheimer’s.

The compound used in the current study, a specific inhibitor of the kinase PERK which is a key mediator of the pathway leading to the cell death, had originally been developed by GlaxoSmithKline for a different purpose. It is able to enter the brain and block the degenerative process. However, it cannot be used in humans because of serious side effects found in the mice, including weight loss and mild diabetes, due to damage to the pancreas.

Professor Giovanna Mallucci, who led the team at the Medical Research Council (MRC) Toxicology Unit at the University, 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 MRC’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.”


Moreno et al. Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice. Sci Transl Med 9 October 2013. Vol. 5, Issue 206, p. 206ra138
DOI: 10.1126/scitranslmed.3006767


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