Enzyme Found Disrupting Nerve Cell Communication in Alzheimer’s Disease

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.

In Alzheimer’s disease, communication between nerve cells (shown here in green) is disrupted by an aberrant protein called SNO-Cdk5. (Credit: Tomohiro Nakamura, Sanford-Burnham Medical Research Institute)
 
 

To this end, a research team led by Stuart A. Lipton, M.D., Ph.D. at Sanford-Burnham Medical Research Institute (Sanford-Burnham) 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 online the week of August 15 in the Proceedings of the National Academy of Sciences, 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.

“After NO is attached to Cdk5, it then jumps like a ‘hot potato’ to another protein called Drp1, disrupting its function and fragmenting mitochondria, the energy powerhouse of nerve cells. When the mitochondria are damaged, the synapses, which normally require a lot of energy for their function, are destroyed. This scenario disrupts communication between nerve cells, and thus memory and cognitive ability in Alzheimer’s disease,” said Dr. Lipton, professor and director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging and Stem Cell Research Center. Dr. Lipton is also a neurologist who sees Alzheimer’s disease patients in his own clinical practice, and is credited with characterizing and developing memantine (Namenda®), the latest FDA-approved drug for Alzheimer’s disease.

In the current study, Cdk5 is shown to perform a new function not previously known — the ability to transfer NO from one protein to another. Until now, Cdk5 was only known to influence the function of other proteins by tagging them with phosphate groups in a process known as phosphorylation. The new study shows that the addition of NO sends Cdk5 into overdrive and allows it to also S-nitrosylate other proteins, in this case Drp1 on mitochondria. Most notably, the transfer of NO from SNO-Cdk5 to Drp1 triggers the loss of synapses, the part of a nerve cell that transmits electrochemical signals to other nerve cells. Loss of synapses is known to correlate with the degree of cognitive decline in Alzheimer’s disease.

Taking the study a step further, the team compared SNO-Cdk5 levels in brain tissue from healthy people and from Alzheimer’s disease patients. SNO-Cdk5 was dramatically elevated in human brains with Alzheimer’s disease.

“Our experiments using human brain tissue from patients with Alzheimer’s disease give this finding clear clinical relevance,” Dr. Lipton said. “SNO-Cdk5 could provide a new target for treating this devastating condition.”

As many as 5.3 million Americans are living with Alzheimer’s, currently the seventh-leading cause of death in the United States. This study was funded by the National Institutes of Health (NIH). Co-authors include Jing Qu, Tomohiro Nakamura, Gang Cao, Emily A. Holland, Scott R. McKercher, and Stuart A. Lipton, all located at Sanford-Burnham in La Jolla, Calif.

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Researchers identify micro-RNA that regulates learning processes, Alzheimer’s

Proteins are the molecular machines of the cell. They transport materials, cleave products or transmit signals – and for a long time, they have been a main focus of attention in molecular biology research. In the last two decades, however, another class of critically important molecules has emerged: small RNA molecules, including micro-RNAs. It is now well established that micro-RNAs play a key role in the regulation of cell function.

“A micro-RNA regulates the production of an estimated 300-400 proteins. This class of molecules can be regarded as a switch that coordinates the transition of cells from one state to another,” explains Prof. Dr. Andr- Fischer, scientist at the German Center for Neurodegenerative Diseases (DZNE) and Speaker of the DZNE site Guttingen.

He and his team have identified a micro-RNA that regulates the learning processes and probably plays a central role in Alzheimer’s disease. The researchers have shown that there is too much of a micro-RNA called “miRNA 34c” in mouse models of Alzheimer’s disease, and decreasing the level of miRNA 34c in these mice can restore their learning ability.

The scientists have identified a new target molecule that might be important for diagnosis and treatment of Alzheimer’s disease. The studies were carried out in collaboration with scientists at the European Neuroscience Institute Guttingen, the Guttingen University, the DZNE site in Munich and researchers from Switzerland, USA and Brazil.

miRNA 34c was identified using a highly complex method called “massive parallel sequencing”. With this technology, Fischer and his colleagues captured the complete RNA composition in the hippocampus – the learning region of the brain – and compared this with the RNA of the entire brain. They showed that miRNA 34c is enriched in the hippocampus, especially in during the time window of a few hours after a learning phase.

“We suspect that the function of micro-RNA 34c is to switch off a whole range of gene products that are turned on in the learning process,” Fischer said.

Too much miRNA 34c would then lead to a blockade of learning – which is exactly what was shown in subsequent experiments. In old mice, which do not learn as easily as their younger counterparts, there was indeed too much miRNA 34c.

The miRNA-34c level was also elevated in mice that are used as specific research models of Alzheimer’s disease. These mice carry a genetic mutation that can cause Alzheimer’s in humans and show disturbances of memory function. Moreover, miRNA 34c seems to not only play a role in mice. Fischer and his colleagues showed these levels are also elevated in the brains of Alzheimer’s patients.

In further mouse experiments, the researchers showed that miRNA 34c is actually causally involved in the pathogenesis of Alzheimer’s disease and memory disorders. An artificial increase of miRNA-34c level in normal mice results in memory impairment in the animals.

Secondly, as Fischer and his colleagues have shown, lowering miRNA-34c levels can restore learning ability in mouse models of Alzheimer’s disease and in older mice. “Neurodegenerative diseases like Alzheimer’s are associated with many factors.

We hope that with the identification of micro-RNA 34c, we have found an important mediator of pathogenesis,” says Fischer. “Micro-RNA 34c would then be a good candidate for the development of drugs against Alzheimer’s.”

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Award-Winning Research Points Toward Targeted Alzheimer’s Vaccine

Oral vaccine targets RAGE and amyloid by using body’s immune system

An accomplice to the protein that causes plaque buildup in Alzheimer’s disease is the focus of a potential new treatment byh Scott Webster. Phil Jones, Georgia Health Sciences University photographer

 An accomplice to the protein that causes plaque buildup in Alzheimer’s disease is the focus of a potential new treatment, according to research by a Georgia Health Sciences University graduate student.

In Alzheimer’s, the amyloid protein can accumulate in the brain instead of being eliminated by the body’s natural defenses, nestling between the neurons and forming impassable plaques.

Amyloid and the way it gets there could be targets for a new vaccine.

“RAGE, or receptor for advanced glycation endproducts, proteins bind to amyloid and transport it into the brain,” said Scott Webster, a fifth-year graduate student who is studying the disease in the lab of Dr. Alvin Terry, Professor of Pharmacology and Toxicology. Research has shown that RAGE may also contribute to the inflammation and damage that amyloid causes to the brain’s nerve cells.

Webster is researching a vaccine that targets RAGE and amyloid by using the body’s own immune system to protect against their over-production and eventual build-up. His work has earned him the 2011 Darrell W. Brann Scholarship in Neuroscience, a $1,000 award honoring an outstanding graduate student on the Augusta, Ga. campus working in neuroscience.

“Unfortunately, all of the vaccines for Alzheimer’s that have been through clinical trials have failed,” he said. “Part of the reason why could be that they’re just not comprehensive enough. Most only target amyloid. Our hope is that by taking a more encompassing approach, we will be more effective. So far, that’s exactly what we’re seeing in our experiments.”

Other vaccines also have multiple side effects, including swelling of the brain. Webster hopes that targeting the RAGE protein and changing how the vaccine is administered will minimize inflammatory side effects.

Another benefit is that the vaccine can be administered orally, since it does not require an adjuvant, which is added to vaccines to enhance the immune response. The digestive tract is one of the body’s largest repositories of human flora, microorganisms that are key to the immune system.

“That’s a relatively new idea,” Webster said. “By using the immune system that’s endogenous to our gut, we can skew the body’s response away from the inflammatory and toward a more robust antibody response, bypassing some of the side effects.”

Early results have shown improved cognition and memory in animal models of Alzheimer’s, something Webster considers a sort of personal crusade.

“I have watched a close family friend suffer from the disease and saw how devastating it was,” he said. “The family is caring for this person and yet the person doesn’t even remember who his own family is. It’s a heartbreaking process to watch.”

Even with promising results, he cautioned of unknowns about the potential vaccine.

“We need to move on to larger animal studies. We have a lot we still don’t know about the vaccine itself. For example, we know that amyloid and RAGE bind together, but we don’t know why the binding creates such a stable complex. We have these end points, but we still don’t know some of the basic science that needs to be known so that we can push ahead.”

In addition to the Brann Scholarship, Webster’s research has earned him an invitation to the St. Jude National Graduate Student Symposium and the National Institutes of Health National Graduate Student Research Conference. He is also a two-time recipient of the Lowell Greenbaum Award for Research Excellence in Pharmacology.

Potential Target for Treating Common Form of Early-Onset Dementia Identified

No cure exists for frontotemporal dementia, which strikes between the ages of 40 and 64 and accounts for at least one in four cases of early-onset dementia. Caused by the death of cells in the front and sides of the brain, the disease can lead to dramatic changes in a patient’s personality and behavior, including the loss of the ability to communicate.

Now UCLA scientists have discovered that a key signaling pathway plays an important role in the brain disorder and may offer a potential target for treatment. The journal Neuron publishes the findings in its Sept. 22 edition.

“A family history exists for nearly half of the frontotemporal dementia patients we see, suggesting a genetic component for the disease,” explained Dr. Daniel Geschwind, who holds the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics, and is a professor of neurology at the David Geffen School of Medicine at UCLA and a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA. “Our goal was to reveal what happens on a molecular level that causes the neuron death leading to this devastating disease.”

Earlier studies had linked the brain disorder with a mutation in the gene for a protein called granulin that regulates cell growth and survival. Previous research showed that the gene mutation reduced the amount of granulin by half.

“Until now, little has been known about granulin’s function in the brain,” said Geschwind. “We wanted to explore whether a granulin shortage kick-starts the cell death that precedes dementia. We also were searching for naturally occurring protective responses that we could target to help alleviate the disease’s symptoms.”

Geschwind and his colleagues examined granulin’s role from three fronts: in cell culture, in a gene-knockout mouse model and in post-mortem brain tissue from dementia patients.

“Cell death is easy to observe in brain tissue removed from patients after their death,” said Geschwind. “We pursued two other approaches to determine the mechanism behind brain-cell survival and uncover how early it occurs in the disease.”

The UCLA team performed a genetic analysis of granulin-deficient neurons made from human brain stem cells. The scientists used a powerful technique that allowed them to see the entire genome and search for networks of highly correlated genes.

“We discovered that a drop in granulin sabotaged brain cells’ survival and boosted activity of Wnt, a major signaling pathway,” said Geschwind. “Within this pathway, we identified a major increase in a specific receptor that Wnt binds to on the cell surface. This change occurred early in the disease process in both living mice and culture.”

The scientists found that Wnt signaling through the receptor FZD2 was heightened in granulin-deficient mice. They demonstrated that reducing the receptor resulted in greater cell death while increasing it promoted neuron survival.

“We believe that Wnt boosts FZD2 to help protect brain-cell survival during the early stages of dementia,” said Geschwind. “Our findings suggest that increasing this receptor and other parts of the Wnt pathway may provide a new drug target to treat this disease.”

Geschwind’s coauthors included Ezra Rosen, Eric Wexler, Revital Versano, Giovanni Coppola, Fuying Gao, Kellen Winden and Michael Oldham, all of UCLA; and Lauren Herl Martens, Ping Zou and Robert Farese Jr., of UC San Francisco.

The research was supported by grants from the Consortium for Frontotemporal Dementia, National Institute of Aging, National Institute for Neurological Disease and Stroke, National Institute of Mental Health and the John Douglas French Alzheimer’s Foundation.

 

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Subjective Memory Impairment as a Sign of Alzheimer’s Disease

Scientists at Charité — Universitätsmedizin Berlin, Universitätsklinikum Bonn, and Deutsches Zentrum für Neurodegenerative Erkrankungen in Bonn succeeded for the first time in demonstrating that even in merely subjective cases of memory deterioration changes may be visible in certain brain structures.

The study, published in the current issue of the Archives of General Psychiatry on August 1, supports the model whereby subjective memory impairment can be the first manifestation of Alzheimer’s disease. Although not every individual with subjective memory impairment develops Alzheimer’s disease, almost every patient with Alzheimer’s disease initially develops subjective memory impairment that has not been possible to objectify until now.

Typical brain changes offer an approach toward early diagnosis. (Credit: Image courtesy of Charité – Universitätsmedizin Berlin)

 

Alzheimer’s disease is the most frequent cause of dementia. The key to dementia prevention is diagnosis as early as possible. For some years now it has been a confirmed fact that in individuals who already have a slight objective memory impairment it is possible to diagnose the onset of Alzheimer’s disease by means of imaging procedures and cerebrospinal fluid tests. However, it would be even better to reveal signs of such a disease at an even earlier stage.

Researchers from Bonn and Berlin have now taken an important step in this direction: They found signs of brain function disorders in individuals who merely experience a subjective deterioration in memory without any reduced performance been detectable in objective behavioral tests.

The team led by Professor Frank Jessen (Bonn), Privatdozentin Susanne Erk, and Professor Henrik Walter (both at Charité) were able to demonstrate by functional magnetic resonance imaging that elderly people with subjective memory impairment already show functional alterations in the region of the hippocampus. The hippocampus is a brain structure that is responsible, inter alia, for memory formation and is affected first in Alzheimer’s disease. In an experiment, individuals with subjective memory impairment manifested reduced activation of the hippocampus during a memory task. At the same time there was increased activation of the right frontal brain.

“This increased frontal activation is probably of a compensatory nature,” says Prof. Walter, head of the Mind and Brain Research Division at the Charité Department of Psychiatry and Psychotherapy. “It compensates for the hippocampal deficit, which may explain why in the memory tests of this group the performance was no worse than in a same-age control group without subjective memory impairment.” Prof. Frank Jessen, Department of Psychiatry and Psychotherapy at the Universitätsklinik Bonn, believes there may be clinical relevance for the future as well: “At least we have thus come closer to our goal of in future backing up the hitherto purely clinical early diagnosis of subjective memory impairment in suspected cases of Alzheimer’s disease by conducting noninvasive objective brain examinations.”

 

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Advances in Research Into Alzheimer’s Disease

Advances in research into Alzheimer’s disease: transporter proteins at the blood CSF barrier and vitamin D may help prevent amyloid β build up in the brain.

Advancing age is a major risk factor for Alzheimer’s disease and is associated with build- up of the peptide amyloid β in the brain. New research published in BioMed Central’s open access journal Fluids and Barriers of the CNS shows that removal of amyloid β from the brain depends on vitamin D and also on an age-related alteration in the production of transporter proteins which move amyloid β in and out of the brain.

Low levels of vitamin D are thought to be involved in age-related decline in memory and cognition and are also associated with Alzheimer’s disease. Researchers from Tohoku University, Japan, looked at the mechanism behind this and found that vitamin D injections improved the removal of amyloid β from the brain of mice.

Prof Tetsuya Terasaki said, “Vitamin D appears increase transport of amyloid β across the blood brain barrier (BBB) by regulating protein expression, via the vitamin D receptor, and also by regulating cell signaling via the MEK pathway. These results lead the way towards new therapeutic targets in the search for prevention of Alzheimer’s disease.”

The transport of amyloid β across the BBB is known to be orchestrated by transporter proteins such as LRP-1 and P-gp, which move amyloid β out of the brain, and RAGE, which controls influx. Looking at the transport of amyloid β from blood to cerebrospinal fluid (CSF), and from CSF to blood, researchers from Rhode Island Hospital and The Warren Alpert Medical School, found that LRP-1 and P-gp at the blood-cerebrospinal fluid barrier (BCSFB), increased with age so increasing removal of amyloid β from the CSF and brain.

Prof Gerald Silverberg said, “While increased production of transporter proteins at the blood CSF barrier may help amyloid β removal from the older brain, production of these proteins eventually fails. This failure may be an important event in brain function as we age and for people with Alzheimer’s disease.”

 

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Destructive Amyloid-Beta Protein May Also Be Essential for Normal Brain Function

Alzheimer’s disease is thought to be caused by the build-up of a brain peptide called amyloid-beta. That’s why eliminating the protein has been the focus of almost all drug research pursuing a cure for the devastating neurodegenerative condition.

But that may be counterproductive, says Dr. Inna Slutsky of Tel Aviv University’s Department of Physiology and Pharmacology, Sackler Faculty of Medicine. Her recent research demonstrates that amyloid-beta is also necessary to maintain proper brain functioning.

These findings may shake the foundations of Alzheimer’s research.

In a new study published this month in Nature Neuroscience, Dr. Slutsky finds that amyloid-beta is essential for normal day-to-day information transfer through nerve cell networks in the brain. “If this protein is removed from the brain,” says Dr. Slutsky, “as some drugs in development attempt to do, it may cause an impairment of neuronal function, as well as a further and faster accumulation of amyloid-beta in Alzheimer’s.”

A reset button for drug researchers

Without amyloid-beta, a normal product of cellular metabolism, one’s ability to learn and remember could be profoundly damaged, so drugs currently in development to eliminate amyloid-beta could be rendered obsolete. With Dr. Slutsky’s research, a leap in understanding the cause and development of Alzheimer’s disease, however, new, more effective drug therapies could be developed.

A model of the human brain. New research suggests that amyloid-beta peptide — the buildup of which in the brain is believed to cause Alzheimer’s disease — is also necessary to maintain proper brain functioning. (Credit: iStockphoto/Mark Evans)

By studying synapses in brain slices of healthy mice and in neuronal networks growing in vitro, Dr. Slutsky and her team determined that there is an optimal amount of amyloid-beta needed to keep the neurons working well. Her students Efrat Abramov and Iftach Dolev found that if this precise balance is even slightly disturbed, the effectiveness of information transfer between neurons is greatly impaired.

“Synapses where neurons meet work as filters of information,” says Dr. Slutsky. “What is really exciting for us is the fact that amyloid-beta peptide, believed to be toxic, regulates the type of information that neurons transfer.”

A new way to prevent Alzheimer’s?

The study of Dr. Slutsky’s team suggests that the amyloid-beta protein belongs to endogenous molecules regulating normal synaptic transmission in the hippocampus, a brain region involved in learning and memory function. “There is a long list of neuromodulators that help synapses optimize information transfer,” she says. “Intriguingly, amyloid-beta seems to be able to modulate this filter and shape its properties.”

The new study is discouraging news for those Alzheimer drugs that attempt to block or remove the amyloid-beta aggregation process currently in clinical trials, Dr. Slutsky believes. “Our data shows that after the release of amyloid-beta, synaptic activity in the neurons is increased through a positive feedback loop. Disrupting this positive feedback loop, I believe, is the key for prevention of the earliest signs of Alzheimer’s.”

Dr. Slutsky completed her post-doctoral work at MIT four years ago, specializing in cellular mechanisms that maintain memory function. She received an international Young Investigator Award in Alzheimer’s disease from the Rosalinde and Arthur Gilbert Foundation of American Federation for Aging Research in 2008.

In addition to Dr. Slutsky, Dolev and Abramov, authors of the paper also include Hilla Fogel and Eyal Ruff of TAU’s Sackler Faculty of Medicine, and Giuseppe Ciccotosto of the University of Melbourne in Australia.

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Diabetes May Significantly Increase Your Risk Of Dementia

People with diabetes appear to be at a significantly increased risk of developing dementia, according to a study published in the September 20, 2011, print issue of Neurology®, the medical journal of the American Academy of Neurology (AAN).

“Our findings emphasize the need to consider diabetes as a potential risk factor for dementia,” said study author Yutaka Kiyohara, M.D., Ph.D., of Kyushu University in Fukuoka, Japan. “Diabetes is a common disorder, and the number of people with it has been growing in recent years all over the world. Controlling diabetes is now more important than ever.”

People with diabetes were more likely to develop Alzheimer’s disease and other types of dementia, such as vascular dementia, which occurs when there is damage to blood vessels that eventually deprive the brain of oxygen.

For the study, a total of 1,017 people who were age 60 and older were given a glucose (sugar) tolerance test after an overnight fast to determine if they had diabetes. Study participants were monitored for an average of 11 years and then tested for dementia. During the study, 232 people developed dementia.

The study found that people with diabetes were twice as likely to develop dementia as people with normal blood sugar levels. Of the 150 people with diabetes, 41 developed dementia, compared to 115 of the 559 people without diabetes who developed dementia. The results remained the same after the researchers accounted for factors such as high blood pressure, high cholesterol and smoking. The risk of dementia was also higher in people who did not have diabetes, but had impaired glucose tolerance, or were “pre-diabetes.”

In addition, the study found the risk of developing dementia significantly increased when blood sugar was still high two hours after a meal.

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