Gene therapy for Alzheimer's?

Alzheimer's Disease is the most common form of age-related dementia, affecting an estimated 25 million people worldwide.The pathological hallmarks of this condition, which were described 100 years ago by the German pathologist Alois Alzheimer, consist of plaques of amyloid beta protein and neurofibrillary tangles made of tau protein. These insoluble deposits accumulate within the brain, and are believed to be toxic to nerve cells.

Now, researchers from Harvard Medical School show that the amyloid plaques in mice with Alzheimer's-like pathology can be effectively cleared by implanting cells expressing an enzyme that breaks down the amyloid beta protein. The findings, which were published yesterday in the open access journal PLoS Medicine, suggest that it may be possible to develop a gene therapy for Alzheimer's Disease.

Dennis Selkoe and his colleagues performed their experiments on a strain of genetically engineered mice that express human APP, the presursor protein from which amyloid beta is generated. As they age, these animals develop amyloid plaques within their brains.

Selkoe and his colleauges removed skin cells called fibroblasts from the experimental mice, and then inserted into them a viral vector containing a gene encoding an enzyme called neprilysin, which degrades the amyloid beta protein. The cells were then injected into the animals' brains. A group of control mice were injected with fibroblasts transfected with vectors lacking the neprilysin gene.

28 days after implantation of the cells, the brains of the mice were dissected, and antibody staining was used to determine the extent to which the amyloid plaques had been cleared from the brains of the experimental animals.

It was found that there was a significant reduction in plaques in the hippocampus, the part of the brain into which the cells had been implanted. In the graft site itself, a 72% reduction in plaques was observed, compared to the hippocampus of animals injected with a vector that did not contain the neprilysin gene. There was also a significant reduction (55%) in plaques in areas adjacent to the graft site.

The method used by Selkoe's team, called ex vivo gene delivery, has to date been successfully used in clinical trials for human conditions such as amyotrophic lateral sclerosis and various eye diseases.

One major obstacle to developing an ex vivo gene therapy treatment for Alzheimer's Disease is the size of the human brain. Although the neprilysin secreted by the implanted cells was found to degrade the plaques in areas next to the graft site, a therapeutic effect in humans would  probably require enzyme activity throughout a much broader area.

This could, however, possibly be achieved by implanting neprilysin-producing cells into the cerebrospinal fluid (CSF), or into the walls of the brain ventricles, where the CSF is produced. Because amyloid beta protein circulates in the CSF, such an approach might be beneficial. The current study shows that further investigation into such a therapy is warranted.


Hemming, M. L., et al. (2007). Reducing amyloid plaque burden via ex vivo gene delivery of an amyloid beta-degrading protease: A novel therapeutic approach to Alzheimer's Disease. PLoS Medicine 4 (8): e262. [Full text]


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