New study explains why promising dementia drugs failed in clinical trials

December 5, 2013
Neural stem cells generated from iPS cells derived from a patient with Alzheimer’s disease. Once established such neural stem cells can be used to continuously generate neurons for drug testing and disease modeling. Depicted is an immunofluorescence staining where proteins characteristic of neural stem cells are labeled with fluorescing antibodies (Nestin in green, Dach1 in red). The cells show a rosette-like growth pattern, which is typical for early neural stem cells. Credit: Stem Cell Reports, Mertens et al.

Alzheimer's disease is the most common cause of dementia among older people, yet there currently are no effective drugs to stop, slow or prevent disease progression. A study online December 5th in the ISSCR's journal Stem Cell Reports, published by Cell Press, provide interesting clues on why non-steroidal anti-inflammatory drugs (NSAIDs), which have successfully treated molecular signs of Alzheimer's disease in cell and animal models, eventually failed in clinical studies. Whereas the compounds worked in non-neuronal cells lines typically used in pharmaceutical drug screening, the authors found that human neurons are resistant to this class of drugs.

"The results of our study are significant for future drug development approaches, because they imply that compound screening and validation studies might be much more reliable if they are conducted using the human cell type affected by the disease in question," says Oliver Brüstle of the University of Bonn who senior-authored the study together with his colleague Philipp Koch.

Alzheimer's disease is characterized by the accumulation of compounds called Aβ peptides in the brain, and this process is believed to cause progressive neurodegeneration and dementia. Longer Aβ42 peptides tend to aggregate more than shorter Aβ40 peptides, and a high ratio of Aβ42 to Aβ40 is used as a biomarker of Alzheimer's disease. NSAIDs have been found to modulate Aß processing, resulting in decreased Aß42/40 ratios in several cell and animal models of the disease. But for previously unknown reasons, these drugs failed to delay in phase 2 and phase 3 clinical trials.

Neurons generated from neural stem cells. These are the cells, which were used for drug testing. They show the typical neuronal morphology with long processes. Again, this is an immunofluorescence analysis, this time with antibodies to the neuronal proteins beta-III-tubulin (green) and tau (red); many processes contain both proteins and thus appear yellow. Credit: Stem Cell Reports, Mertens et al.

Brüstle and Koch revisited this enigma and for the first time directly tested the effectiveness of NSAIDs in human neurons. They used an induced (iPSC) approach, which involved taking skin from patients with Alzheimer's disease, reprogramming these cells into embryonic-like stem cells, and then converting them into neurons. These neurons showed high Aβ42/Aβ40 ratios, which failed to respond to therapeutically relevant concentrations of NSAIDs. In contrast, commonly used non-neuronal cell lines typically employed in drug screening responded strongly, thereby wrongly suggesting efficacy of the drugs.

"The results highlight the importance of testing compounds directly in authentic human cells", says Jerome Mertens, lead author of the study.

"Until recently, it was difficult to obtain native human neurons for drug testing in the field of neurodegenerative diseases. With recent advances in iPSC technology, it has become possible to generate virtually unlimited numbers of human neurons from individual patients," Brüstle says. "We hope that our findings will promote the use of stem cell-derived neurons for in the field of neurological disorders."

Explore further: The benefits of a spotless mind

More information: dx.doi.org/10.1016/j.stemcr.2013.10.011

Related Stories

The benefits of a spotless mind

November 15, 2013
Alzheimer's disease is an age-related memory disorder characterized by the accumulation of clumps of the toxic amyloid-β (Aβ) protein fragment in the extracellular space around neurons in the brain. Drugs that help to 'clean ...

Rare disease yields clues about broader brain pathology

November 21, 2013
(Medical Xpress)—Alexander disease is a devastating brain disease that almost nobody has heard of—unless someone in the family is afflicted with it. Alexander disease strikes young or old, and in children destroys white ...

Scientists map molecular mechanism that may cause toxic protein buildup in dementing disorders

August 29, 2013
There is no easy way to study diseases of the brain. Extracting brain cells, or neurons, from a living patient is difficult and risky, while examining a patient's brain post-mortem usually only reveals the disease's final ...

Reinventing drug discovery: Promising drug target for ALS

April 18, 2013
Using a new stem-cell based drug screening technology with the potential to reinvent and greatly reduce the cost of the way new pharmaceuticals are developed, Harvard Stem Cell Institute (HSCI) researchers have found a compound ...

Alzheimer's leaves clues in blood

June 4, 2013
Alzheimer researchers in Spain have taken a step closer to finding a blood test to help in the diagnosis of Alzheimer's disease.

Alzheimer's, schizophrenia, and autism now can be studied with mature brain cells reprogrammed from skin cells

June 6, 2013
Difficult-to-study diseases such as Alzheimer's, schizophrenia, and autism now can be probed more safely and effectively thanks to an innovative new method for obtaining mature brain cells called neurons from reprogrammed ...

Recommended for you

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

New animal models for hepatitis C could pave the way for a vaccine

July 19, 2017
They say that an ounce of prevention is worth a pound of cure. In the case of hepatitis C—a disease that affects nearly 71 million people worldwide, causing cirrhosis and liver cancer if left untreated—it might be worth ...

Omega-3 fatty acids fight inflammation via cannabinoids

July 18, 2017
Chemical compounds called cannabinoids are found in marijuana and also are produced naturally in the body from omega-3 fatty acids. A well-known cannabinoid in marijuana, tetrahydrocannabinol, is responsible for some of its ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.