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Although the exact pathophysiological processes underlying Alzheimer’s disease are a mystery,the hallmark pathology involves neuritic plaques. At the core of these neuritic plaques is β-amyloid protein. Although the protein is a normal constituent of many cells, it aggregates into fibrils in Alzheimer’s disease.
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| Cascade to dementia? The conversion of Aβ1-42 peptides to toxic amyloid fibrils, which begins a long process of calcium influx and gene expression—possibly the first steps in Alzheimer’s disease—may be disrupted by decoy peptides generated by Vernon Ingram and colleagues. (Adapted from Blanchard, B. J., et al. J. Alz. Dis. 2000, 2, 137–149.) |
Recent work at the Massachusetts Institute of Technology supports the idea that β-amyloid aggregates are, indeed, toxic to human neurons. The investigators may have identifieda mechanism underlying β-amyloid-induced neuronal toxicity (J. Alz. Dis. 2000, 2, 137–149) as well as a means of protecting neurons from the deleterious effects of β-amyloid accumulation.
Using hNT cells, a differentiated teratocarcinoma cell line, Vernon Ingram and colleagues applied β-amyloid to cells in culture. As β-amyloid aggregates formed and fibrils came in direct contact with cells, a rise in intracellular calcium was observed. Because sustained elevated calcium levels contribute to neuronal death, the scientists investigated the mechanism by which β-amyloid fibrils induce calcium influx. They found that two compounds that block calcium entry via AMPA/kainate channels eliminated the calcium influx that otherwise occurred in the presence of β-amyloid aggregates. This result implicates these channels as potential routes of calcium entry into β-amyloid-exposed cells.
The investigators went on to develop a series of “decoy peptides” that coaggregate with β-amyloid, several of which prevented intracellular calcium entry. According to Ingram, “We are not yet sure whether decoy peptides stabilize fibrils or modify the β-sheet secondary structure formed by fibrils.”
Suitable as potential therapeutic candidates, the peptides studied were comprised of d-amino acids, and as such, are resistant to gastrointestinal digestion. Moreover, the short length of the peptides (pentamers to nonamers) may permit modifications that allow penetration of the blood–brain barrier. Although these results were obtained with neuronal cells in vitro, potential implications for novel therapeutic strategies abound.
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