A 'switch' in Alzheimer's and stroke patient brains that prevents the generation and survival of neurons

July 3, 2014
Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

A new study by researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) has identified a chemical "switch" that controls both the generation of new neurons from neural stem cells and the survival of existing nerve cells in the brain. The switch that shuts off the signals that promote neuron production and survival is in abundance in the brains of Alzheimer's patients and stroke victims. The study, published July 3 in Cell Reports, suggests that chemical switch, MEF2, may be a potential therapeutic target to protect against neuronal loss in a variety of neurodegenerative diseases, such as Alzheimer's, Parkinson's and autism.

"We have shown that when nitric oxide (NO)—a highly reactive free radical—reacts with MEF2, MEF2 can no longer bind to and activate the genes that drive neurogenesis and neuronal survival," said Stuart Lipton, M.D., Ph.D., director and professor in the Neuroscience and Aging Research Center at Sanford-Burnham, and a practicing clinical neurologist. "What's unique here is that a single alteration to MEF2 controls two distinct events—the generation of new neurons and the survival of existing neurons," added Lipton, who is senior author of the study.

In the brain, transcription factors are critical for linking external stimuli to protein production, enabling neurons to adapt to changing environments. Members of the MEF2 family of have been shown to play an important role in neurogenesis and neuronal survival, as well as in the processes of learning and memory. And, mutations of the MEF2 gene have been associated with a range of neurodegenerative disorders, including Alzheimer's and autism.

The process of NO-protein modifications—known as S-nitrosylation—was first described by Lipton and collaborators some 20 years ago. S-nitrosylation has important regulatory functions under normal physiological conditions throughout the body. However, with aging, environmental toxins, or stress-related injuries, abnormal S-nitrosylation reactions can occur, contributing to disease pathogenesis.

"Our laboratory had previously shown that S-nitrosylation of MEF2 controlled neuronal survival in Parkinson's disease," said Lipton. "Now we have shown that this same reaction is more ubiquitous, occurring in other neurological conditions such as stroke and Alzheimer's disease. While the major gene targets of MEF2 may be different in various diseases and brain areas, the remarkable new finding here is that we may be able to treat each of these neurological disorders by preventing a common S-nitrosylation modification to MEF2.

"The findings suggest that the development of a small therapeutic molecule—one that can cross the blood-brain barrier and block S-nitrosylation of MEF2 or in some other way increase MEF2 transcriptional activity—could promote new brain cell growth and protect existing cells in several neurodegenerative disorders," added Lipton.

"We have already found several such molecules in our high-throughput screening and drug discovery efforts, so the potential for developing new drugs to attack this pathway is very exciting," said Lipton.

Explore further: Chemical reaction keeps stroke-damaged brain from repairing itself

Related Stories

Chemical reaction keeps stroke-damaged brain from repairing itself

February 4, 2013
Nitric oxide, a gaseous molecule produced in the brain, can damage neurons. When the brain produces too much nitric oxide, it contributes to the severity and progression of stroke and neurodegenerative diseases such as Alzheimer's. ...

Neurons made from stem cells drive brain activity after transplantation in laboratory model

November 15, 2012
(Medical Xpress)—Researchers and patients look forward to the day when stem cells might be used to replace dying brain cells in Alzheimer's disease and other neurodegenerative conditions. Scientists are currently able to ...

Research finds enzyme disrupting nerve cell communication in Alzheimer's disease

August 15, 2011
Alzheimer's disease is characterized by abnormal proteins that stick together in little globs, disrupting cognitive function (thinking, learning, and memory). These sticky proteins are mostly made up of beta-amyloid peptide. ...

How mom's immune system is linked to autism risk

September 23, 2013
(Medical Xpress)—Activating a mother's immune system during her pregnancy disrupts the development of neural cells in the brain of her offspring and damages the cells' ability to transmit signals and communicate with one ...

Recommended for you

Noninvasive eye scan could detect key signs of Alzheimer's years before patients show symptoms

August 17, 2017
Cedars-Sinai neuroscience investigators have found that Alzheimer's disease affects the retina—the back of the eye—similarly to the way it affects the brain. The study also revealed that an investigational, noninvasive ...

Could olfactory loss point to Alzheimer's disease?

August 16, 2017
By the time you start losing your memory, it's almost too late. That's because the damage to your brain associated with Alzheimer's disease (AD) may already have been going on for as long as twenty years. Which is why there ...

New Machine Learning program shows promise for early Alzheimer's diagnosis

August 15, 2017
A new machine learning program developed by researchers at Case Western Reserve University appears to outperform other methods for diagnosing Alzheimer's disease before symptoms begin to interfere with every day living, initial ...

Brain scan study adds to evidence that lower brain serotonin levels are linked to dementia

August 14, 2017
In a study looking at brain scans of people with mild loss of thought and memory ability, Johns Hopkins researchers report evidence of lower levels of the serotonin transporter—a natural brain chemical that regulates mood, ...

Alzheimer's risk linked to energy shortage in brain's immune cells

August 14, 2017
People with specific mutations in the gene TREM2 are three times more likely to develop Alzheimer's disease than those who carry more common variants of the gene. But until now, scientists had no explanation for the link.

Scientists reveal role for lysosome transport in Alzheimer's disease progression

August 7, 2017
Researchers from Yale University School of Medicine have discovered that defects in the transport of lysosomes within neurons promote the buildup of protein aggregates in the brains of mice with Alzheimer's disease. The study, ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

JVK
not rated yet Jul 03, 2014
"We identified candidate transcription factors for OR gene expression and among them confirmed by chromatin immunoprecipitation the binding of TBP, EBF1 (OLF1), and MEF2A to OR promoters." http://www.ncbi.n...22194471

In the context of epigenetic effects of odors on de novo creation of olfactory receptor genes, the conserved molecular mechanisms that run amok in neurodegnerative diseases can be linked to the decline in olfactory acuity and specificity,

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.