Neuroscience

A molecular compound developed by Saint Louis University scientists restored learning, memory and appropriate behavior in a mouse model of Alzheimer’s disease, according to findings in the May issue of the Journal of Alzheimer’s Disease. The molecule also reduced inflammation in the part of the brain responsible for learning and memory.

The paper, authored by a team of scientists led by Susan Farr, Ph.D., research professor of geriatrics at Saint Louis University, is the second mouse study that supports the potential therapeutic value of an antisense compound in treating Alzheimer’s disease in humans.

"It reversed learning and memory deficits and brain inflammation in mice that are genetically engineered to model Alzheimer’s disease," Farr said. "Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer’s disease."

Farr cautioned that the experiment was conducted in a mouse model. Like any drug, before an antisense compound could be tested in human clinical trials, toxicity tests need to be completed.

Antisense is a strand of molecules that bind to messenger RNA, launching a cascade of cellular events that turns off a certain gene.

In this case, OL-1 blocks the translation of RNA, which triggers a process that keeps excess amyloid beta protein from being produced. The specific antisense significantly decreased the overexpression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in the brain of patients who have Alzheimer’s disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Previously they had tested the substance in a mouse model that has a natural mutation causing it to overproduce mouse amyloid beta. Like people who have Alzheimer’s disease, both types of mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus — the part of the brain responsible for learning and memory.

"To be effective in humans, OL-1 would need to be effective at suppressing production of human amyloid beta protein," Farr said.

Scientists compared the mice that were genetically engineered to overproduce human amyloid beta protein with a wild strain, which served as the control. All of the wild strain received random antisense, while about half of the genetically engineered mice received random antisense and half received OL-1.

The mice were given a series of tests designed to measure memory, learning and appropriate behavior, such as going through a maze, exploring an unfamiliar location and recognizing an object.

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. Learning and memory were the same among genetically engineered mice that received OL-1 and wild mice that received random antisense.

They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body. They found where the drug was injected had little effect on learning and memory.

"Our findings reinforced the importance of amyloid beta protein in the Alzheimer’s disease process. They suggest that an antisense that targets the precursor to amyloid beta protein is a potential therapy to explore to reversing symptoms of Alzheimer’s disease," Farr said.

In his search to understand the role and function of brain waves, neuroscientist Ole Jensen (Radboud University) postulates a new theory on how the alpha wave controls attention to visual signals. His theory is published in Trends in Neurosciences on May 20. Alpha waves appear to be even more active and important than Jensen already thought.

Our brain cells ‘spark’ all the time. From this electronic activity brain waves emerge: oscillations at different band widths. And like a radio station uses different frequencies to carry specific information far away from the emitting source, so does the brain. And just like radio listeners with a certain musical preference tune in to the frequency that carries the music they prefer, brain area’s tune into the wave length relevant for their functioning.

Alpha waves aren’t boring
Ole Jensen, professor of Neuronal Oscillations at Radboud University’s Donders Institute for Brain, Cognition and Behaviour, tries to figure out how this network of sending and receiving information through oscillations works in detail. Earlier he discovered a novel role of the alpha wave that was long thought to be a boring wave, emerging when the brain runs idle and a person is dozing off. Jensen shifted this interpretation by showing the importance of the alpha frequency: it helps to shut down irrelevant brain area’s for a certain task. It helps us concentrate on what is really important at that moment.

To do list
In the Trends in Neurosciences paper that appeared today, Jensen postulates a new theory for how this actually works given a visual task. ‘We think that different phases of the alpha wave encode for different parts of a visual scene. It helps breaking down the visual information into small jobs and then perform those tasks in a specific order. A to do list for your visual attention system: focus on the face, focus on the hand, focus on the glass, look around. And then all over again.’

Jensen is now planning to test this new interpretation of the alpha wave in both animals and humans.

Scientists at the University of Pittsburgh School of Medicine have identified for the first time a key molecular mechanism by which the abnormal protein found in Huntington’s disease can cause brain cell death. The results of these studies, published today in Nature Neuroscience, could one day lead to ways to prevent the progressive neurological deterioration that characterizes the condition.

Huntington’s disease patients inherit from a parent a gene that contains too many repeats of a certain DNA sequence, which results in the production of an abnormal form of a protein called huntingtin (HTT), explained senior investigator Robert Friedlander, M.D., UPMC Professor of Neurosurgery and Neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But until now, studies have not suggested how HTT could cause disease.

“This study connects the dots for the first time and shows how huntingtin can cause problems for the mitochondria that lead to the death of neurons,” Dr. Friedlander said. “If we can disrupt the pathway, we may be able to identify new treatments for this devastating disease.”

Examination of brain tissue samples from both mice and human patients affected by Huntington’s disease showed that mutant HTT collects in the mitochondria, which are the energy suppliers of the cell. Using several biochemical approaches in follow-up mouse studies, the research team identified the mitochondrial proteins that bind to mutant HTT, noting its particular affinity for TIM23, a protein complex that transports other proteins from the rest of the cell into the mitochondria.

Further investigation revealed that mutant HTT inhibited TIM23’s ability to transport proteins across the mitochondrial membrane, slowing metabolic activity and ultimately triggering cell-suicide pathways. The team also found that mutant HTT-induced mitochondrial dysfunction occurred more often near the synapses, or junctions, of neurons, likely impairing the neuron’s ability to communicate or signal its neighbors.

To verify the findings, the researchers showed that producing more TIM23 could overcome the protein transport deficiency and prevent cell death.

“We learned also that these events occur very early in the disease process, not as the result of some other mutant HTT-induced changes,” Dr. Friedlander said. “This means that if we can find ways to intervene at this point, we may be able to prevent neurological damage.”

The team’s next steps include identifying exact binding sites and agents that can influence the interactions of HTT and TIM23.

Perhaps one of the keys to good health isn’t just what you eat but how you taste it.

Taste buds – yes, the same ones you may blame for that sweet tooth or French fry craving – may in fact have a powerful role in a long and healthy life – at least for fruit flies, say two new studies that appear in the Proceedings of the National Academy of Sciences of the United States of America.

Researchers from the University of Michigan, Wayne State University and Friedrich Miescher Institute for Biomedical Research in Switzerland found that suppressing the animal’s ability to taste its food –regardless of how much it actually eats – can significantly increase or decrease its length of life and potentially promote healthy aging.
 
Bitter tastes could have negative effects on lifespan, sweet tastes had positive effects, and the ability to taste water had the most significant impact – flies that could not taste water lived up to 43% longer than other flies. The findings suggest that in fruit flies, the loss of taste may cause physiological changes to help the body adapt to the perception that it’s not getting adequate nutrients.

In the case of flies whose loss of water taste led to a longer life, authors say the animals may attempt to compensate for a perceived water shortage by storing greater amounts of fat and subsequently using these fat stores to produce water internally. Further studies are planned to better explore how and why bitter and sweet tastes affect aging.

“This brings us further understanding about how sensory perception affects health. It turns out that taste buds are doing more than we think,” says senior author of the University of Michigan-led study Scott Pletcher, Ph.D., associate professor in the Department of Molecular and Integrative Physiology and research associate professor at the Institute of Gerontology.

“We know they’re able to help us avoid or be attracted to certain foods but in fruit flies, it appears that taste may also have a very profound effect on the physiological state and healthy aging.”
 
Pletcher conducted the study with lead author Michael Waterson, a Ph.D graduate student in U-M’s Cellular and Molecular Biology Program.  

“Our world is shaped by our sensory abilities that help us navigate our surroundings and by dissecting how this affects aging, we can lay the groundwork for new ideas to improve our health,” says senior author of the other study, Joy Alcedo, Ph.D, assistant professor in the Department of Biological Sciences at Wayne State University, formerly of the Friedrich Miescher Institute for Biomedical Research in Switzerland. Alcedo conducted the research with lead author Ivan Ostojic, Ph.D., of the Friedrich Miescher Institute for Biomedical Research in Switzerland.

Recent studies suggest that sensory perception may influence health-related characteristics such as athletic performance, type II diabetes, and aging. The two new studies, however, provide the first detailed look into the role of taste perception.

“These findings help us better understand the influence of sensory signals, which we now know not only tune an organism into its environment but also cause substantial changes in physiology that affect overall health and longevity,” Waterson says. “We need further studies to help us apply this knowledge to health in humans potentially through tailored diets favoring certain tastes or even pharmaceutical compounds that target taste inputs without diet alterations.”

In Parkinson’s disease (PD), dopamine-producing nerve cells that control our movements waste away. Current treatments for PD therefore aim at restoring dopamine contents in the brain. In a new study from Lund University, researchers are attacking the problem from a different angle, through early activation of a protein that improves the brain’s capacity to cope with a host of harmful processes. Stimulating the protein, called Sigma-1 receptor, sets off a battery of defence mechanisms and restores lost motor function. The results were obtained in mice, but clinical trials in patients may not be far away.

By activating the Sigma-1 receptor, a versatile protein involved in many cellular functions, levels of several molecules that help nerve cells build new connections increased, inflammation decreased, while dopamine levels also rose. The results, published in the journal Brain, show a marked improvement of motor symptoms in mice with a Parkinson-like condition that had been treated with a Sigma-1-stimulating drug for 5 weeks.

This treatment has never before been studied in connection with Parkinson’s disease. However, various publications linked to stroke and motor neurone disease have reported positive results with drugs that stimulate the Sigma-1 receptor, and a biotech company in the US will soon begin clinical trials on Alzheimer’s patients. The fact that substances stimulating this protein are already available for clinical use is a major advantage, according to Professor M. Angela Cenci Nilsson, head of the research team at Lund University.

“It is a huge advantage that these substances have already been tested in people and approved for clinical application. It means that we already know that the body tolerates this treatment. Clinical trials for Parkinson’s disease could theoretically start any time”.

Boosting the brain’s in-built defence mechanisms with approaches like this is a rather new idea in Parkinson’s research. Professor Cenci Nilsson, however, believes that the number of targets for future treatments is increasing as we learn more and more about the complex effects of PD on many different types of cells in the brain.

“The motor improvements we have seen in mice are disproportionately large compared to the recovery of dopamine levels. We believe this is because the treatment has protected the brain against a series of indirect consequences triggered by the Parkinson-like lesion. For example, we know today that a loss of dopamine causes the target neurons to lose synapses, and also alters both neural pathways and non-neuronal cells in the brain. Since the Sigma-1 receptor is widely expressed in many cell types, the treatment could intervene in many of these damaging processes “.

The treatment was shown to be significantly more effective when started at the beginning of the most aggressive phase of dopamine cell death. As a future potential therapy for Parkinson’s disease, this treatment would therefore need to be started as soon as possible after diagnosis in order to deliver maximum impact.

“In order to accelerate a possible clinical translation of our findings, we will now seek further evidence in support of this type of treatment. We are now discussing various opportunities with different collaborating partners, and we will try to procure funding for clinical studies in Parkinson´s disease as soon as possible”, concludes M. Angela Cenci Nilsson.

A biologist and a psychologist at the University of York have joined forces with a drug discovery group at Lundbeck in Denmark to develop a potential route to new therapies for the treatment of Parkinson’s Disease (PD).

Dr Chris Elliott, of the Department of Biology, and Dr Alex Wade, of the Department of Psychology, have devised a technique that could both provide an early warning of the disease and result in therapies to mitigate its symptoms.

In research reported in Human Molecular Genetics, they created a more sensitive test which detected neurological changes before degeneration of the nervous system became apparent.

In laboratory tests using fruit flies, the researchers discovered that a human genetic mutation that causes Parkinson’s amplified visual signals in young flies dramatically. This resulted in loss of vision in later life.

Working with researchers from the Danish pharmaceutical company, H.Lundbeck A/S, they tested a new drug that targets the Parkinson’s mutation in flies. This drug prevented the abnormal changes in the flies’ visual function.

It is the first time that the compound has been used in vivo and its effectiveness was analysed using the new, sensitive technique devised by Dr Wade. This was originally used for measuring vision in people with eye disease and epilepsy.

Dr Elliott, who is part-funded by Parkinson’s UK, said: “If this kind of drug proves to be successful in clinical trials, it would have the potential to bring long-lasting relief from PD symptoms and fewer side effects than existing levadopa therapy.”

Dr Wade added: “This technique forms a remarkable bridge between human clinical science and animal research. If it proves successful in the future, it could open the door to a new way of studying a whole range of neurological diseases.”

Senior Vice President, Research at Lundbeck, Kim Andersen, said:  “This new research may prove to be groundbreaking in the understanding and treatment of Parkinson’s disease. Science does not currently have answers for what happens in the brain before and during the disease, but these discoveries may bring us closer to this understanding. This may also give us the opportunity to revolutionize the diagnosis and treatment of Parkinson’s disease, for the benefit of patients and their families.”

Mice crippled by an autoimmune disease similar to multiple sclerosis (MS) regained the ability to walk and run after a team of researchers led by scientists at The Scripps Research Institute (TSRI), University of Utah and University of California (UC), Irvine implanted human stem cells into their injured spinal cords.

Remarkably, the mice recovered even after their bodies rejected the human stem cells. “When we implanted the human cells into mice that were paralyzed, they got up and started walking a couple of weeks later, and they completely recovered over the next several months,” said study co-leader Jeanne Loring, a professor of developmental neurobiology at TSRI.

Thomas Lane, an immunologist at the University of Utah who co-led the study with Loring, said he had never seen anything like it. “We’ve been studying mouse stem cells for a long time, but we never saw the clinical improvement that occurred with the human cells that Dr. Loring’s lab provided,” said Lane, who began the study at UC Irvine.

The mice’s dramatic recovery, which is reported online ahead of print by the journal Stem Cell Reports, could lead to new ways to treat multiple sclerosis in humans.

"This is a great step forward in the development of new therapies for stopping disease progression and promoting repair for MS patients,” said co-author Craig Walsh, a UC Irvine immunologist.

Stem Cell Therapy for MS

MS is an autoimmune disease of the brain and spinal cord that affects more than a half-million people in North America and Europe, and more than two million worldwide. In MS, immune cells known as T cells invade the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating on nerve fibers called myelin. Affected nerve fibers lose their ability to transmit electrical signals efficiently, and this can eventually lead to symptoms such as limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression.

Current therapies, such as interferon beta, aim to suppress the immune attack that strips the myelin from nerve fibers. But they are only partially effective and often have significant adverse side effects. Loring’s group at TSRI has been searching for another way to treat MS using human pluripotent stem cells, which are cells that have the potential to transform into any of the cell types in the body.

Loring’s group has been focused on turning human stem cells into neural precursor cells, which are an intermediate cell type that can eventually develop into neurons and other kinds of cells in the nervous system. In collaboration with Lane’s group, Loring’s team has been testing the effects of implanting human neural precursor cells into the spinal cords of mice that have been infected with a virus that induces symptoms of MS.

A Domino Effect

The transformation that took place in the largely immobilized mice after the human neural precursor cells were injected into the animals’ damaged spinal cords was dramatic. “Tom called me up and said, ‘You’re not going to believe this,’” Loring said. “He sent me a video, and it showed the mice running around the cages. I said, ‘Are you sure these are the same mice?’”

Even more remarkable, the animals continued walking even after the human cells were rejected, which occurred about a week after implantation. This suggests that the human stem cells were secreting a protein or proteins that had a long-lasting effect on preventing or impeding the progression of MS in the mice, said Ron Coleman, a TSRI graduate student in Loring’s lab who was first author of the paper with Lu Chen of UC Irvine. “Once the human stem cells kick that first domino, the cells can be removed and the process will go on because they’ve initiated a cascade of events,” said Coleman.

The scientists showed in the new study that the implanted human stem cells triggered the creation of white blood cells known as regulatory T cells, which are responsible for shutting down the autoimmune response at the end of an inflammation. In addition, the implanted cells released proteins that signaled cells to re-myelinate the nerve cells that had been stripped of their protective sheaths.

A Happy Accident

The particular line of human neural precursor cells used to heal the mice was the result of a lucky break. Coleman was using a common technique for coaxing human stem cells into neural precursor cells, but decided partway through the process to deviate from the standard protocol. In particular, he transferred the developing cells to another Petri dish.

“I wanted the cells to all have similar properties, and they looked really different when I didn’t transfer them,” said Coleman, who was motivated to study MS after his mother died from the disease. This step, called “passaging,” proved key. “It turns out that passaging alters the types of proteins that the cells express,” he said.

Loring called the creation of the successful neural precursor cell line a “happy accident.” “If we had used common techniques to create the cells, they wouldn’t have worked,” she said. “We’ve shown that now. There are a dozen different ways to make neural precursor cells, and only this one has worked so far. We now know that it is incredibly important to make the cells the same way every time.”

Hot On the Trail

The team is now working to discover the particular proteins that its unique line of human precursor cells release. One promising candidate is a class of proteins known as transforming growth factor beta, or TGF-B, which other studies have shown is involved the creation of regulatory T cells. Experiments by the scientists showed that the human neural precursor cells released TGF-B proteins while they were inside the spinal cords of the impaired mice. However, it’s also likely that other, as yet unidentified, protein factors may also be involved in the mice’s healing.

If the team can pinpoint which proteins released by the neural precursor cells are responsible for the animals’ recovery, it may be possible to devise MS treatments that don’t involve the use of human stem cells. “Once we identify the factors that are responsible for healing, we could make a drug out of them,” said Lane. Another possibility, Loring said, might be to infuse the spinal cords of humans affected by MS with the protein factors that promote healing.

A better understanding of what makes these human neural precursor cells effective in mice will be key to developing either of these therapies for humans. “We’re on the trail now of what these cells do and how they work,” Loring said.

In 2008, researchers at the Perelman School of Medicine at the University of Pennsylvania showed that mutations in two proteins associated with familial Alzheimer’s disease (FAD) disrupt the flow of calcium ions within neurons. The two proteins interact with a calcium release channel in an intracellular compartment. Mutant forms of these proteins that cause FAD, but not the normal proteins, result in exaggerated calcium signaling in the cell.

Now, the same team, led by J. Kevin Foskett, PhD, chair of Physiology, and a graduate student, Dustin Shilling, has found that suppressing the hyperactivity of the calcium channels alleviated FAD-like symptoms in mice models of the disease. Their findings appear this week in the Journal of Neuroscience.

Current therapies for Alzheimer’s include drugs that treat the symptoms of cognitive loss and dementia, and drugs that address the pathology of Alzheimer’s are experimental. These new observations suggest that approaches based on modulating calcium signaling could be explored, says Foskett.

The two proteins, called PS1 and PS2 (presenilin 1 and 2), interact with a calcium release channel, the inositol trisphosphate receptor (IP3R), in the endoplasmic reticulum. Mutant PS1 and PS2 increase the activity of the IP3R, in turn increasing calcium levels in the cell. “We set out to answer the question: Is increased calcium signaling, as a result of the presenilin-IP3R interaction, involved in the development of familial Alzheimer’s disease symptoms, including dementia and cognitive deficits?” says Foskett. “And looking at the findings of these experiments, the answer is a resounding ‘yes.’”

Exaggerated intracellular calcium signaling is a robust phenomenon seen in cells expressing FAD-causing mutant presenilins, in both human cells in culture and in mice. The team used two FAD mouse models to look for these connections. Specifically, they found that reducing the expression of IP3R1, the dominant form of this receptor in the brain, by 50 percent, normalized the exaggerated calcium signaling observed in neurons of the cortex and hippocampus in both mouse models.

(Image caption: Amyloid-beta (antibody 12F4) and hyper-phosphorylated tau (antibody AT180) immunostaining of hippocampus from 18-month-old mice. Amyloid plaques (top row) and intracellular tau tangles (bottom row) in the 3xTg mouse were strongly reduced by genetic deletion of 50% of the IP3R1 in the 3xTg/Opt mouse. Wild-type (WT) and Opt mice expressing 50% of InsP3R exhibited no pathology. Credit: J. Kevin Foskett, PhD & Dustin Shilling, Perelman School of Medicine, University of Pennsylvania)

In addition, using 3xTg mice – animals that contain presenilin 1 with an FAD mutation, as well as expressed mutant human tau protein and APP genes — the team observed that the reduced expression of IP3R1 profoundly decreased amyloid plaque accumulation in brain tissue and the hyperphosphorylation of tau protein, a biochemical hallmark of advanced Alzheimer’s disease. Reduced expression of IP3R1 also rescued defective electrical signaling in the hippocampus, as well and memory deficits in the 3xTg mice, as measured by behavioral tests. 

“Our results indicate that exaggerated calcium signaling, which is associated with presenilin mutations in familial Alzheimer’s disease, is mediated by the IP3R and contributes to disease symptoms in animals,” says Foskett. “Knowing this now, the IP3 signaling pathway could be considered a potential therapeutic target for patients harboring mutations in presenilins linked to AD.”

 “The ‘calcium dysregulation’ hypothesis for inherited, early-onset familial Alzheimer’s disease has been suggested by previous research findings in the Foskett lab. Alzheimer’s disease affects as many as 5 million Americans, 5 percent of whom have the familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.

“The ‘amyloid hypothesis’ that postulates that the primary defect is an accumulation of toxic amyloid in the brain has long been used to explain the cause of Alzheimer’s”, says Foskett. In his lab’s 2008 Neuron study, cells that carried the disease-causing mutated form of PS1 showed increased processing of amyloid beta that depended on the interaction of the PS proteins with the IP3R. This observation links dysregulation of calcium inside cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer’s disease.

Clinical trials for AD have largely been directed at reducing the amyloid burden in the brain. So far, says Foskett, these trials have failed to demonstrate therapeutic benefits. One idea is that the interventions started too late in the disease process. Accordingly, anti-amyloid clinical trials are now underway using asymptomatic FAD patients because it is known that they will eventually develop the disease, whereas predicting who will develop the common form of AD is much less certain.

“There has been an assumption that FAD is simply AD with an earlier, more aggressive onset,” says Foskett. “However, we don’t know if the etiology of FAD pathology is the same as that for common AD. So the relevance of our findings for understanding common AD is not clear. What’s important, in my opinion, is to recognize that AD could be a spectrum of diseases that result in common end-stage pathologies. FAD might therefore be considered an orphan-disease, and it’s important to find effective treatments, specifically for these patients - ones that target the IP3R and calcium signaling.”

Stimulation of a certain population of neurons within the brain can alter the learning process, according to a team of neuroscientists and neurosurgeons at the University of Pennsylvania. A report in the Journal of Neuroscience describes for the first time that human learning can be modified by stimulation of dopamine-containing neurons in a deep brain structure known as the substantia nigra. Researchers suggest that the stimulation may have altered learning by biasing individuals to repeat physical actions that resulted in reward.

"Stimulating the substantia nigra as participants received a reward led them to repeat the action that preceded the reward, suggesting that this brain region plays an important role in modulating action-based associative learning," said co-senior author Michael Kahana, PhD, professor of Psychology in Penn’s School of Arts and Sciences.

Eleven study participants were all undergoing deep brain stimulation (DBS) treatment for Parkinson’s disease. During an awake portion of the procedure, participants played a computer game where they chose between pairs of objects that carried different reward rates (like choosing between rigged slot machines in a casino). The objects were displayed on a computer screen and participants made selections by pressing buttons on hand-held controllers. When they got a reward, they were shown a green screen and heard a sound of a cash register (as they might in a casino). Participants were not told which objects were more likely to yield reward, but that their task was to figure out which ones were “good” options based on trial and error. 

When stimulation was provided in the substantia nigra following reward, participants tended to repeat the button press that resulted in a reward. This was the case even when the rewarded object was no longer associated with that button press, resulting in poorer performance on the game when stimulation was given (48 percent accuracy), compared to when stimulation was not given (67 percent).

"While we’ve suspected, based on previous studies in animal models, that these dopaminergic neurons in the substantia nigra - play an important role in reward learning, this is the first study to demonstrate in humans that electrical stimulation near these neurons can modify the learning process," said the study’s co-senior author Gordon Baltuch, MD, PhD, professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania. “This result also has possible clinical implications through modulating pathological reward-based learning, for conditions such as substance abuse or problem gambling, or enhancing the rehabilitation process in patients with neurological deficits.”

Much like using dimmer switches to brighten or darken rooms, biochemists have identified a protein that can be used to slow down or speed up the growth of brain tumors in mice.

Brain and other nervous system cancers are expected to claim 14,320 lives in the United States this year.

The results of the preclinical study led by Eric J. Wagner, Ph.D., and Ann-Bin Shyu, Ph.D., of The University of Texas Health Science Center at Houston (UTHealth) and Wei Li, Ph.D., of Baylor College of Medicine appear in the Advance Online Publication of the journal Nature.

“Our work could lead to the development of a novel therapeutic target that might slow down tumor progression,” said Wagner, assistant professor in the Department of Biochemistry and Molecular Biology at the UTHealth Medical School.

Shyu, professor and holder of the Jesse H. Jones Chair in Molecular Biology at the UTHealth Medical School, added, “This link to brain tumors wasn’t previously known.”

“Its role in brain tumor progression was first found through big data computational analysis, then followed by animal-based testing. This is an unusual model for biomedical research, but is certainly more powerful, and may lead to the discovery of more drug targets,” said Li, an associate professor in the Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology at Baylor. 

Wagner, Shyu, Li and their colleagues discovered a way to slow tumor growth in a mouse model of brain cancer by altering the process by which genes are converted into proteins.

Appropriately called messenger RNA for short, these molecules take the information inside genes and use it to make body tissues. While it was known that the messenger RNA molecules associated with the cancerous cells were shorter than those with healthy cells, the mechanism by which this occurred was not understood.

The research team discovered that a protein called CFIm25 is critical to keeping messenger RNA long in healthy cells and that its reduction promotes tumor growth. The key research finding in this study was that restoring CFIm25 levels in brain tumors dramatically reduced their growth.

“Understanding how messenger RNA length is regulated will allow researchers to begin to develop new strategies aimed at interfering with the process that causes unusual messenger RNA shortening during the formation of tumors,” Wagner said.

Additional preclinical tests are needed before the strategy can be evaluated in humans.

“The work described in the Nature paper by Drs. Wagner and Shyu stems from a high-risk/high-impact Cancer Prevention & Research Institute of Texas (CPRIT) proposal they submitted together and received several years ago,” said Rod Kellems, Ph.D., professor and chairman of the Department of Biochemistry and Molecular Biology at the UTHealth Medical School.

“Their research is of fundamental biological importance in that it seeks to understand the role of messenger RNA length regulation in gene expression,” Kellems said.  “Using a sophisticated combination of biochemistry, genetics and bioinformatics, their research uncovered an important role for a specific protein that is linked to glioblastoma tumor suppression.”

Bottom Line: Cerebral small-vessel disease (SVD) and Alzheimer disease (AD) pathology appear to be associated.

Author:  Maartje I. Kester, M.D., Ph.D., of the VU University Medical Center, Amsterdam, the Netherlands, and colleagues.

Background: AD is believed to be caused by the buildup of amyloid protein in the brain and tau tangles. Previous studies have suggested that SVD and vascular risk factors increase the risk of developing AD. In both SVD and vascular dementia (VaD), signs of AD pathology have been seen. But it remains unclear how the interaction between SVD and AD pathology leads to dementia.

How the Study Was Conducted: Authors examined the association between SVD and AD pathology by looking at magnetic resonance imaging (MRI)-based microbleeds (MB), white matter hyperintensities (WMH) and lacunes (which are measures for SVD) along with certain protein levels in cerebrospinal fluid (CSF) which reflect AD pathophysiology in patients with AD, VaD and healthy control patients. The authors also examined the relationship of apolipoprotein E (APOE) Ɛ4 genotype, a well-known risk factor for AD.

Results: The presence of both MBs and WMH was associated with lower CSF levels of Aβ42, suggesting a direct relationship between SVD and AD. Amyloid deposits also appear to be abnormal in patients with SVD, especially in (APOE) Ɛ4 carriers.

Discussion: “Our study supports the hypothesis that the pathways of SVD and AD pathology are interconnected. Small-vessel disease could provoke amyloid pathology while AD-associated cerebral amyloid pathology may lead to auxiliary vascular damage.”