The first experimental drug to boost brain synapses lost in Alzheimer’s disease has been developed by researchers at Sanford-Burnham. The drug, called NitroMemantine, combines two FDA-approved medicines to stop the destructive cascade of changes in the brain that destroys the connections between neurons, leading to memory loss and cognitive decline.
Photomicrograph of nerve cell during an electrical recording (left), fluorescently labeled nerve cell (right)
Neuron
In stroke and other neurological disorders, nitric oxide damages neurons and blocks the brain’s ability to self-repair
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. Researchers at Sanford-Burnham Medical Research Institute recently discovered that nitric oxide not only damages neurons, it also shuts down the brain’s repair mechanisms. Their study was published February 4 by the Proceedings of the National Academy of Sciences.
“In this study, we’ve uncovered new clues as to how natural chemical reactions in the brain can contribute to brain damage—loss of memory and cognitive function—in a number of diseases,” said Stuart A. Lipton, M.D., Ph.D., director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and a clinical neurologist.
Lipton led the study, along with Sanford-Burnham’s Tomohiro Nakamura, Ph.D., who added that these new molecular clues are important because “we might be able to develop a new strategy for treating stroke and other disorders if we can find a way to reverse nitric oxide’s effect on a particular enzyme in nerve cells.”
Stuart A. Lipton, M.D., Ph.D., director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and a clinical neurologist
Neurons made from stem cells drive brain activity after transplantation in laboratory model
Originally published November 15, 2012
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 make neurons and other brain cells from stem cells, but getting these neurons to properly function when transplanted to the host has proven to be more difficult. Now, researchers at Sanford-Burnham Medical Research Institute have found a way to stimulate stem cell-derived neurons to direct cognitive function after transplantation to an existing neural network. The study was published November 7 in the Journal of Neuroscience.
Left: Control cells exposed to hydrogen peroxide. Right: Cells treated with carnosic acid are protected from hydrogen peroxide. Live cells are stained green, dead cells are stained red.
Researchers discover that carnosic acid, a component of the herb rosemary, promotes eye health in rodents—providing a possible new approach for treating conditions such as age-related macular degeneration.
Herbs widely used throughout history in Asian and early European cultures have received renewed attention by Western medicine in recent years. Scientists are now isolating the active compounds in many medicinal herbs and documenting their antioxidant and anti-inflammatory activities. In a study published in the journal Investigative Ophthalmology & Visual Science, Stuart A. Lipton, M.D., Ph.D. and colleagues at Sanford-Burnham Medical Research Institute report that carnosic acid, a component of the herb rosemary, promotes eye health.
Lipton’s team found that carnosic acid protects retinas from degeneration and toxicity in cell culture and in rodent models of light-induced retinal damage. Their findings suggest that carnosic acid may have clinical applications for diseases affecting the outer retina, including age-related macular degeneration, the most common eye disease in the U.S.
Stuart A. Lipton, M.D., Ph.D., director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and a clinical neurologist
Sanford-Burnham researchers convince transplanted stem cell-derived neurons to direct cognitive function—getting us a step closer to using these cells to treat Alzheimer’s disease and other neurodegenerative conditions.
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 make neurons and other brain cells from stem cells, but getting these neurons to properly function when transplanted to the host has proven to be more difficult. Now, researchers at Sanford-Burnham Medical Research Institute have found a way to stimulate stem cell-derived neurons to direct cognitive function after transplantation to an existing neural network. The study was published November 7 in the Journal of Neuroscience.
Congratulations to John B. Gurdon and Shinya Yamanaka on winning the 2012 Nobel Prize in Physiology or Medicine! They received the award today for their “discovery that mature cells can be reprogrammed to become pluripotent.” In other words, these scientists figured out how to turn a normal adult cell, such as a skin cell, into a stem cell that has the potential to become any other type of cell in the body. Read below to learn more about stem cells and how they are revolutionizing medical research.
What are stem cells?
Stem cells are special because each is like a blank slate. Once it’s given the proper instruction, a stem cell can specialize and become any type of cell in the body—brain, heart, muscle, and more. Stem cells also have the ability to reproduce themselves indefinitely, renewing the supply.
Are there different types of stem cells?
Embryonic stem cells only exist during an organism’s development, when it is an embryo. These cells are pluripotent, meaning they have the capacity to become any cell type in the body.
Adult stem cells exist in fully developed organisms. They are more limited than embryonic stem cells—they are multipotent rather than pluripotent. These stem cells usually can only become a few types of specialized cells, based on the tissue from which they originate.
Induced pluripotent stem cells (iPSCs) are pluripotent, much like embryonic stem cells. iPSCs are produced in the laboratory by genetically reprogramming any adult cell, such as a skin cell.
On Memorial Day, members of our military—including those who have sacrificed their lives or have returned to us with injuries or illness—will receive much-deserved thanks and recognition. Whether you attend a parade, observe a moment of silence for those lost, or simply shake a soldier’s hand and say, “thank you,” you will find your way of expressing your gratitude. At Sanford-Burnham, we support the U.S. armed services by doing what we do best: science.
Sanford-Burnham’s headquarters in San Diego County place it in the midst of one of the largest active duty military populations in the country and the largest concentration of soldiers wounded in combat. Additionally, both states where Sanford-Burnham has locations, California and Florida, are among those with the largest populations of veterans. So the men and women who defend us are always on our minds. In honor of Memorial Day weekend, we have chosen to highlight some of the ways we strive to defend them in return.
Erin Singer (right), with Ilyas Singec, Ph.D. and Rajesh Ambasudhan, Ph.D., two scientists in Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research
Most interns come and go within a few months, learning from hands-on experience and making important contacts for the future. Erin Singer, who recently completed her second Sanford-Burnham internship, has created a visually stunning image of stem cells that will be displayed at the Institute in the building housing the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research. The image illustrates the beauty of human biology and serves as a reminder of Erin’s contributions to the important research conducted at the center.
Dr. John Reed and Dr. Stuart Lipton
Sanford-Burnham is a highly collaborative institute, embracing opportunities to connect with scientists nationwide, so perhaps the greatest honor our researchers can receive is the recognition of their peers. Our CEO John C. Reed, M.D., Ph.D., and Director of our Del E. Webb Neuroscience, Aging and Stem Cell Research Center, Stuart A. Lipton, M.D., Ph.D., have been named as Fellows of the American Association for the Advancement of Science (AAAS). Fellows are recognized for meritorious efforts to advance science or its applications. This year’s honorees were formally announced today in the AAAS News & Notes section of the journal Science.
Neurons derived from embryonic stem cells
When neurons that make a chemical called dopamine are slowly destroyed, nerve cells in that part of the brain cannot properly send the messages that would normally control muscle function. As the damage gets worse with time, a person experiences tremors and movement becomes difficult. This is Parkinson’s disease.
In short, Parkinson’s patients need more dopamine. Or, better yet, new neurons that produce dopamine on their own. In a paper published August 25 in the journal PLoS ONE, a team led by Dr. Stuart Lipton, director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, demonstrates how this therapeutic approach might be possible.
Crystal Structure of Anthrax Lethal Factor complexed with a small molecule inhibitor
As the United States pauses to observe the 10th anniversary of the September 11th terrorist attacks, we reflect on the research advances that contribute to new counterterrorism measures—understanding anthrax, for example—and the health of our soldiers in Iraq and Afghanistan, including under-studied conditions such as traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Here are a few examples, and these only cover discoveries made at Sanford-Burnham since September 11, 2001. Can you think of more? Please share your thoughts in the comments below.
Neurons (Image courtesy of the Lipton lab)
Imagine the ability to take skin cells from a patient with Alzheimer’s disease, convert them directly into brain cells, and then study how the disease progresses in those cells—which still contain the patient’s DNA—all in the lab, with minimal invasiveness on the part of the patient. Then imagine taking those same brain cells and testing novel but risky drugs that could cure the devastating disease—again, in the safety of a dish in the lab.
Researchers are on their way to achieving this remarkable milestone. Dr. Stuart Lipton at Sanford-Burnham, Dr. Sheng Ding at the Gladstone Institutes, and their collaborators recently figured out how to reprogram skin cells directly into functioning neurons. The study was published online July 28 in the journal Cell Stem Cell.
“This technology should allow us to very rapidly model neurodegenerative diseases in a dish by making nerve cells from individual patients in just a matter of days, rather than the months required previously,” Dr. Lipton says in a statement released by the Gladstone Institutes.
The paper is one of several recent studies that are all zeroing in on a long-sought-after advance in stem cell science: the potential to obtain unlimited numbers of brain cells from an easily accessible tissue such as the skin.
Dr. Evan Snyder (right) interviews Dr. Stuart Lipton in Medscape's "Developments to Watch"
Medscape, a physician-oriented website run by WebMD, visited Sanford-Burnham’s La Jolla campus this summer to record interviews with researchers from both Orlando and San Diego for a new online video program called Developments to Watch. The talk show-like discussions are hosted by Dr. Evan Snyder, who directs the Stem Cells and Regenerative Biology Program at Sanford-Burnham. The first episode, A New Frontier in Alzheimer’s Disease, is now available. In the video, Dr. Snyder speaks with Dr. Stuart Lipton, director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, about his work on Alzheimer’s disease. They discuss what new findings—and potential treatments—are on the horizon and how they might impact patients.
A user name and password are required to access Medscape, but the site and content are free. New installments will be added monthly.
Watch the video, then come back here to let us know what you think!
For more about our research on Alzheimer’s disease, check out these blog posts:
Getting to the root of Alzheimer’s disease
Diagnosing Alzheimer’s Earlier
New Partnership Targets Brain Conditions
Safely Treating Alzheimer’s Disease
Saying NO to Alzheimer’s and Parkinson’s Diseases
Dr. Stuart Lipton
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. A better understanding of these proteins, how they form, and how they affect brain function will no doubt improve the diagnosis and treatment of Alzheimer’s disease.
To this end, a research team led by Dr. Stuart Lipton‘s group found that beta-amyloid-induced destruction of synapses—the connections that mediate communication between nerve cells—is driven by a chemical modification to an enzyme called Cdk5. The team found that this altered form of Cdk5 (SNO-Cdk5) was prevalent in human Alzheimer’s disease brains, but not in normal brains. These results, published August 15 in the Proceedings of the National Academy of Sciences of the USA, suggest that SNO-Cdk5 could be targeted for the development of new Alzheimer’s disease therapies.
Cdk5 is an enzyme known to play a role in normal neuronal survival and migration. In this study, Dr. Lipton and colleagues found that beta-amyloid peptides, the hallmark of Alzheimer’s disease, trigger Cdk5 modification by a chemical process called S-nitrosylation. In this reaction, nitric oxide (NO) is attached to the enzyme, producing SNO-Cdk5 and disrupting its normal activity.
Dr. Randal J. Kaufman
This month we welcomed Sanford-Burnham’s newest faculty member, Dr. Randal J. Kaufman. Dr. Kaufman joins the Institute as professor and director of the Degenerative Disease Research Program, in the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research.
“I am looking forward to the opportunities for collaboration that Sanford-Burnham affords,” Dr. Kaufman says. “This promises to be a very productive environment for my area of research.”
Dr. Kaufman’s current research is focused on understanding the fundamental mechanisms that regulate protein folding and the cellular responses to the accumulation of unfolded proteins within the endoplasmic reticulum (ER). When proteins fail to fold correctly, they don’t work properly. Certain types of misfolded proteins defy eradication by the cellular protein degradation machinery and accumulate with age, causing cellular toxicity. In many degenerative diseases, including neurological, metabolic, genetic and inflammatory diseases, it’s thought that the accumulation of misfolded proteins leads to cellular dysfunction and death.