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Alzheimer's drugs hurt brain?

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. β-amyloidImage: Wikimedia commons, Boku wa Kage This finding "would result in a paradigm shift" in the understanding of the molecular mechanism underlying Alzheimer's disease, said linkurl:Brigita Urbanc,;http://www.phys

By | March 22, 2010

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.
β-amyloid
Image: Wikimedia commons,
Boku wa Kage
This finding "would result in a paradigm shift" in the understanding of the molecular mechanism underlying Alzheimer's disease, said linkurl:Brigita Urbanc,;http://www.physics.drexel.edu/~brigita/ 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 linkurl:Ratnesh Lal;http://www.be.ucsd.edu/faculty/profiles#rlal 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.
**__Related stories:__***linkurl:Alzheimer's clue found;http://www.the-scientist.com/blog/display/55868/
[29th July 2009]*linkurl:New gene in Alzheimer's disease;http://www.the-scientist.com/templates/trackable/display/news.jsp?type=news&o_url=news/display/41520&id=41520
[15th January 2007]*linkurl:Amyloid blockers may be a dead end;http://www.the-scientist.com/blog/display/54239/
[27th January 2008]

Comments

Avatar of: David Adams

David Adams

Posts: 1

March 30, 2010

Great story. It's interesting indeed that the UCSD research found that one of the current Phase III Alzheimer's drugs that works by blocking an enzyme needed to form toxic amyloid beta may also accidently cause harm by increasing the formation of neurotoxic non-amyloid peptides. However, I think two issues have been conflated in this story and need to be clarified. \n\nFirst, although the new findings were described as creating a "paradigm shift in the understanding of the molecular mechanism underlying Alzheimer's disease," to me the paradigm shift should refer to our new understanding that drugs that alter peptide formation in vivo must be evaluated to determine whether they create new non-amyloid neurotoxic peptides. However, that new knowledge doesn't mean that amyloid beta peptides, and the resulting plaque build-up, are not a cause of Alzheimer's disease. \n\nThe UCSD findings do not directly address whether such non-amyloid peptides form in Alzheimer's disease without drug intervention. After all, the toxic non-amyloid peptides we are talking about here appear to be created by the Alzheimer's drugs themselves. What causes Alzheimer's disease in the first place is still likely to be amyloid beta peptides.\n\nSecond, the article did not mention the new finding in view of the failed Phase III trial. Maybe the amyloid lowering drug (secretase inhibitor) failed to help patients because it produced new toxic peptides, even while partially lowering toxic amyloid production. If the Phase III drug created toxic peptides that cause neuronal damage and even cell death, then the patients in the trial may well have shown no behavioral improvements because of that new damage, even if the drug did partially lower amyloid beta production. To say that amyloid beta, therefore, is not a problem, misses the mark. \n\nI think the weight of available data shows that production of toxic amyloid beta (with or without the resulting plaque build-up) is the principle cause of Alzheimer's. The challenge for all of us who work in this area is to develop new strategies and new therapeutics that are beneficial without causing new problems of their own.\n\nDavid Adams\nProfessor of Biology and Biotechnology\nWorcester Polytechnic Institute\n\nwww.wpi.edu
Avatar of: anonymous poster

anonymous poster

Posts: 1

April 5, 2010

The proliferation of unintended consequences is certainly a recurring theme in new drug development. Though David Adams makes an important point here, and perhaps the slant of the original article didn't mean to take so much of the heat of amyloid beta.\n\n\n\n
Avatar of: ADRIAN PREDA

ADRIAN PREDA

Posts: 1

March 1, 2011

While the interpretation of a successful clinical trial is straightforward and it means a passing grade for the supporting theory; the interpretation of a failed clinical trial due to either lack of efficacy or increased rate of adverse effects is much less clear. The failure can indicate that the theory is inadequate, but also that in vitro mechanisms do not translate in the same in vivo, that there is something different about the chosen controls (subject and intervention/placebo) or simply that the trial was poorly executed. Many times it?s impossible to figure out which one of the above is the cause. \n\nThat is why a positive trial is much more informative that a negative one.\n\n

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