FEATURE ARTICLE
Alzheimer's Disease
The molecular origins of the disease are coming to light, suggesting several novel therapies
Vernon Ingram
Making Aβ Peptides Nontoxic
A novel approach to Alzheimer's therapy is needed. Although secretase inhibition and immunotherapy promise to lead to beneficial symptom reduction, they do not yet promise complete elimination. Each treatment appears to have some side effects, and these may limit the allowable range of therapeutic dosages.
One can envisage a drug that would eliminate the neurotoxicity of the aggregated Aβ1-42 peptide itself. Such a drug would have to be given early in order to "detoxify" the gradually accumulating aggregated Aβ peptide before any permanent damage is done to neurons. After all, we do not yet know how to replace dead or dying neurons (although replacement by stem cells might be possible eventually).
The approach taken in my laboratory is to present the aggregating Aβ1-42 peptide with a small molecule that binds to the peptide and forces it to assume a nontoxic structure. My colleagues and I have done this with 16 small peptides (5, 6 or 9 amino acids long), which we call "decoy peptides." They are selected from large libraries of protein fragments by their ability to form a tight association with tagged Aβ1-42. We have found that when presented to the Alzheimer's peptide during aggregation, our decoy peptides completely eliminate the neurotoxic effects, and Aβ1-42 no longer causes massive calcium influx into neuronal cells. We are very excited about these results, and because the peptide binding is so specific, we anticipate a small chance of harmful side effects. These peptides are good candidates for further development, and we have constructed them from d-amino acids (the unnatural form of amino acids) to resist digestion in the body, but a big question remains: Will they get from the gut to the brain? The answer remains to be seen (or engineered).
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