A team of scientists from Cambridge and Sweden have discovered a molecule that can prevent a toxic protein involved Alzheimer's disease from building up in the brain. They found that in test tube studies the molecule not only prevents the protein from forming clumps but can also reverse this process. Then, using fruit flies with Alzheimer's disease, they showed that the same molecule effectively "cures" the insects of the disease.
Alzheimer's disease is the most common neurodegenerative disorder and is linked to the misfolding and aggregation of a small protein known as the amyloid β (Aβ) peptide. Previous studies in animal models have shown that aggregation of Aβ damages neurones (brain cells) causing memory impairment and cognitive deficits similar to those seen in patients with Alzheimer's disease. The mechanisms underlying this damage are, however, still not understood.
The new molecule – designed by scientists in Sweden – is a small protein known as an Affibody (an engineered binding protein). In this new study, researchers at the University of Cambridge and the Swedish University of Agricultural Sciences found that in test-tube experiments this protein binds to the Aβ peptide, preventing it from forming clumps and breaking up any clumps already present.
In a second experiment, they studied the effect of this Affibody in a Drosophila (fruit fly) model of Alzheimer's disease previously developed at Cambridge.
Working with fruit flies that develop the fly equivalent of Alzheimer's because they have been genetically engineered to produce the Aβ protein, they crossed these flies with a second line of flies genetically engineered to produce the Affibody.
They found that offspring – despite producing the Aβ protein – did not develop the symptoms of Alzheimer's disease.
According to lead author Dr Leila Luheshi of the Department of Genetics at University of Cambridge: "When we examined these flies we found that the Affibody not only prevented and reversed the formation of Aβ clumps, it also promoted clearance of the toxic Aβ clumps from the flies' brains."
"Finding a way of preventing these clumps from forming in the brain, and being able to get rid of them, is a promising strategy for preventing Alzheimer's disease. Affibody proteins give us a window into the Alzheimer's brain: by helping us understand how these clumps damage brain cells, they should help us unravel the Alzheimer's disease process."
According to Professor Torleif Härd of the Swedish University of Agricultural Sciences and one of the senior authors of the study: "Our work shows that protein engineering could open up new possibilities in Alzheimer's therapy development."
The study is published today in PLoS Biology.
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Notes to editors:
Leila M. Luheshi et al, 'Sequestration of the Aβ peptide prevents toxicity and promotes degradation in vivo' is published in PLoS Biology on 16 March 2010, http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000334
The study was supported by grants from the Swedish Research Council, the MIVAC Swedish Foundation for Strategic Research Centre, the German Academic Exchange Service, and in the UK by the MRC, the Engineering and Physical Sciences Research Council and the Wellcome Trust.
The work in test tubes was performed by Dr Wolfgang Hoyer and Professor Torleif Härd at the SLU in Sweden. The work with fruit flies was performed by Dr Leila Luheshi and Professor Christopher Dobson at the University of Cambridge. The fruit fly model of AD was originally developed by Dr Damian Crowther and Professor David Lomas at the Department of Medicine, University of Cambridge. The Affibody protein was developed in the laboratory of Professor Stefan Ståhl at the KTH Royal Institute of Technology in Sweden.
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