Drugs being investigated for Alzheimer’s disease may be causing further neural degeneration and cell death, calling for a change in the way Alzheimer’s medications are developed, according to results published in this week’s Proceedings of the National Academy of Sciences.
This finding “would result in a paradigm shift” in the understanding of the molecular mechanism underlying Alzheimer’s disease, said Brigita Urbanc, professor of biophysics at Drexel University, who was not involved in this study, in an email to The Scientist.
Alzheimer’s and other neurodegenerative diseases are thought to be caused by amyloids composed of misfolded beta peptides. The accumulation of these can result in the creation of amyloid plaques in the brain, causing cell death. Higher levels of amyloid beta peptides lead to “earlier onset or more severe systems of Alzheimer’s disease” said Urbanc, and are believed to be the primary cause of the disease.
Current drug candidates for Alzheimer’s disease target these amyloid structures, either by inhibiting the cutting of beta peptides to prevent the formation of amyloids or by creating truncated forms of the beta peptides that do not form amyloids. However, in 2007, one such drug failed Phase III clinical trials because it did not show any cognitive improvement, suggesting that something other than amyloid plaques may be to blame for Alzheimer’s disease.
Combining three dimensional computer simulations with hi-res cell imaging and various cellular assays, nano-biophysicist Ratnesh Lal of the University of California San Diego and his colleagues investigated the structure and function of the truncated peptides, known as nonamyloidgenic peptides, formed by some Alzheimer’s drug candidates. Surprisingly, the researchers found evidence that these smaller peptides were actually part of the problem. The nonamyloidgenic peptides formed ion channels that caused the cells to take-in very high levels of calcium ions, which damaged synaptic efficiency and eventually killed neurons, causing memory loss.
These “smaller and so-called nonamyloidgenic peptides are indeed toxic by themselves,” Lal said. Thus, not only will drug therapies that create nonamyloidgenic peptides not effectively treat the disease, they could increase the speed of degeneration among patients, he said.
Urbanc noted that there are still many unknowns surrounding the mechanism of Alzheimer’s disease, including the impacts of beta peptide structures prior to amyloid formation. It may be possible for “several different toxic structures to co-exist and induce distinct disruptions to neurons,” she said.
“An additional amino acid can change a peptide from somewhat neuroprotective to neurotoxic,” Urbanc added. “The hope is that this inspiring work will give rise to novel studies” that examine the roles of secretases and other peptides in neurodegeneration.
Read more: Alzheimer’s drugs hurt brain? – The Scientist – Magazine of the Life Sciences http://www.the-scientist.com/blog/display/57251/#ixzz0jh8yEIyc
