Use It or Lose It

"Use it or lose it." The saying could apply especially to the brain when it comes to protecting against Alzheimer’s disease. Previous studies have shown that keeping the mind active, exercising and social interactions may help delay the onset of dementia in Alzheimer’s disease.

Now, a new study led by Dennis Selkoe, MD, co-director of the Center for Neurologic Diseases in the Brigham and Women’s Hospital (BWH) Department of Neurology, provides specific pre-clinical scientific evidence supporting the concept that prolonged and intensive stimulation by an enriched environment, especially regular exposure to new activities, may have beneficial effects in delaying one of the key negative factors in Alzheimer’s disease.

The study will be published online on March 6, 2013 in Neuron.

Alzheimer’s disease occurs when a protein called amyloid beta accumulates and forms “senile plaques” in the brain. This protein accumulation can block nerve cells in the brain from properly communicating with one another. This may gradually lead to an erosion of a person’s mental processes, such as memory, attention, and the ability to learn, understand and process information.

The BWH researchers used a wild-type mouse model when evaluating how the environment might affect Alzheimer’s disease. Unlike other pre-clinical models used in Alzheimer’s disease research, wild-type mice tend to more closely mimic the scenario of average humans developing the disease under normal environmental conditions, rather than being strongly genetically pre-disposed to the disease.

Selkoe and his team found that prolonged exposure to an enriched environment activated certain adrenalin-related brain receptors which triggered a signaling pathway that prevented amyloid beta protein from weakening the communication between nerve cells in the brain’s “memory center,” the hippocampus. The hippocampus plays an important role in both short- and long-term memory.

The ability of an enriched, novel environment to prevent amyloid beta protein from affecting the signaling strength and communication between nerve cells was seen in both young and middle-aged wild-type mice.

"This part of our work suggests that prolonged exposure to a richer, more novel environment beginning even in middle age might help protect the hippocampus from the bad effects of amyloid beta, which builds up to toxic levels in one hundred percent of Alzheimer patients," said Selkoe.

Moreover, the scientists found that exposing the brain to novel activities in particular provided greater protection against Alzheimer’s disease than did just aerobic exercise. According to the researchers, this observation may be due to stimulation that occurred not only physically, but also mentally, when the mice moved quickly from one novel object to another.

"This work helps provide a molecular mechanism for why a richer environment can help lessen the memory-eroding effects of the build-up of amyloid beta protein with age," said Selkoe. "They point to basic scientific reasons for the apparent lessening of AD risk in people with cognitively richer and more complex experiences during life."

Alzheimer’s risk gene discovered using imaging method that screens brain’s connections

Scientists at UCLA have discovered a new genetic risk factor for Alzheimer’s disease by screening people’s DNA and then using an advanced type of scan to visualize their brains’ connections.

Alzheimer’s disease, the most common cause of dementia in the elderly, erodes these connections, which we rely on to support thinking, emotion and memory. With no known cure for the disease, the 20 million Alzheimer’s sufferers worldwide lack an effective treatment. And we are all at risk: Our chance of developing Alzheimer’s doubles every five years after age 65.

The UCLA researchers discovered a common abnormality in our genetic code that increases the risk of Alzheimer’s. To find the gene, they used a new imaging method that screens the brain’s connections — the wiring, or circuitry, that communicates information. Switching off such Alzheimer’s risk genes (nine of them have been implicated over the last 20 years) could stop the disorder in its tracks or delay its onset by many years.

The research is published in the March 4 online edition of the journal Proceedings of the National Academy of Sciences.

"We found a change in our genetic code that boosts our risk for Alzheimer’s disease," said the study’s senior author, Paul Thompson, a UCLA professor of neurology and a member of the UCLA Laboratory of Neuro Imaging. "If you have this variant in your DNA, your brain connections are weaker. As you get older, faulty brain connections increase your risk of dementia."

The researchers, Thompson said, screened more than a thousand people’s DNA to find the common “spelling errors” in the genetic code that might heighten their risk for the disease later in life. The new study was the first of its kind to also give each person a “connectome scan,” a special type of scan that measures water diffusion in the brain, allowing scientists to map the strength of the brain’s connections.

The new scan reveals the brain’s circuitry and how information is routed around the brain, in order to discover risk factors for disease. The researchers then combined these connectivity scans with the extensive genomic screening to pinpoint what causes faulty wiring in the brain.

Hundreds of computers, calculating for months, sifted through more than 4,000 brain connections and the entire genetic code, comparing connection patterns in people with different genetic variations. In people whose genetic code differed in one specific gene called SPON1, weaker connections were found between brain centers controlling reasoning and emotion. The rogue gene also affects how senile plaques build up in the brain — one of the hallmarks of Alzheimer’s disease.

"Much of your risk for disease is written in your DNA, so the genome is a good place to look for new drug targets," said Thompson, who in 2009 founded a research network known as Project ENIGMA to pool brain scans and DNA from 26,000 people worldwide. "If we scan your brain and DNA today, we can discover dangerous genes that will undermine your ability to think and plan and will make you ill in the future. If we find these genes now, there is a better chance of new drugs that can switch them off before you or your family get ill."

Developing new therapeutics for Alzheimer’s is a hot area for pharmaceutical research, Thompson said.

It has also been found that the SPON1 gene can be manipulated to develop new treatments for the devastating disease, Thompson noted. When the rogue gene was altered in mice, it led to cognitive improvements and fewer plaques building up in the brain. Alzheimer’s patients show an accumulation of these senile plaques, which are made of a sticky substance called amyloid and are thought to kill brain cells, causing irreversible memory loss and personality changes.

Screening genomes has led to many new drug targets in the treatment of cancer, heart disease, arthritis and brain disorders such as epilepsy. But the UCLA team’s approach — screening genomes and performing brain scans of the same people — promises a faster and more efficient search.

"With a brain scan that takes half an hour and a DNA scan from a saliva sample, we can search your genes for factors that help or harm your brain’s connections," Thompson said. "This opens up a new landscape of discovery in medical science."

Green tea extract interferes with the formation of amyloid plaques in Alzheimer’s disease

Researchers at the University of Michigan have found a new potential benefit of a molecule in green tea: preventing the misfolding of specific proteins in the brain.

The aggregation of these proteins, called metal-associated amyloids, is associated with Alzheimer’s disease and other neurodegenerative conditions.

A paper published recently in the Proceedings of the National Academy of Sciences explained how Life Sciences Institute faculty member Mi Hee Lim and an interdisciplinary team of researchers used green tea extract to control the generation of metal-associated amyloid-β aggregates associated with Alzheimer’s disease in the lab.

The specific molecule in green tea, (—)-epigallocatechin-3-gallate, also known as EGCG, prevented aggregate formation and broke down existing aggregate structures in the proteins that contained metals—specifically copper, iron and zinc.

"A lot of people are very excited about this molecule," said Lim, noting that the EGCG and other flavonoids in natural products have long been established as powerful antioxidants. "We used a multidisciplinary approach. This is the first example of structure-centric, multidisciplinary investigations by three principal investigators with three different areas of expertise."

The research team included chemists, biochemists and biophysicists.

While many researchers are investigating small molecules and metal-associated amyloids, most are looking from a limited perspective, said Lim, assistant professor of chemistry and research assistant professor at the Life Sciences Institute, where her lab is located and her research is conducted.

"But we believe you have to have a lot of approaches working together, because the brain is very complex," she said.

The PNAS paper was a starting point, Lim said, and her team’s next step is to “tweak” the molecule and then test its ability to interfere with plaque formation in fruit flies.

"We want to modify them for the brain, specifically to interfere with the plaques associated with Alzheimer’s," she said.

Lim plans to collaborate with Bing Ye, a neurobiologist in the LSI. Together, the researchers will test the new molecule’s power to inhibit potential toxicity of aggregates containing proteins and metals in fruit flies.

New model could lead to improved treatment for early stage Alzheimer’s

Researchers at the University of Florida and The Johns Hopkins University have developed a line of genetically altered mice that model the earliest stages of Alzheimer’s disease. This model may help scientists identify new therapies to provide relief to patients who are beginning to experience symptoms.

The researchers report their findings in the current issue of The Journal of Neuroscience.

“The development of this model could help scientists identify new ways to enhance brain function in patients in the early stages of the disease,” said David Borchelt, UF professor of neuroscience in the Evelyn F. and William L. McKnight Brain Institute and director of the SantaFe HealthCare Alzheimer’s Disease Research Center. “Such therapies could preserve brain function longer and delay the appearance of more severe symptoms that leave patients unable to care for themselves.”

In the early stages of Alzheimer’s disease, people struggle with and fail to learn new games, rules or technologies because their cognitive flexibility decreases. The degenerative disease continues with memory loss and the decline of other brain functions.

The researchers worked with mice that had specially designed gene fragments derived from bacteria and from humans that allowed the investigators to control the production of a small peptide. The peptide, called amyloid beta peptide, is a short chain of amino acids. Accumulations of this particular peptide in the brain as lesions called plaques occur early  in the progression of Alzheimer’s disease and seem to trigger the early memory problems.

The team regulated the expression of the peptide using antibiotics — when the animals stopped taking the antibiotic, the peptide-producing gene turned on and caused the mice to develop the plaques found in Alzheimer’s patients. After the mice had developed the Alzheimer pathology, the researchers turned the gene back off and observed that the mice showed persistent memory problems that resemble the early stages of the disease.

“This model may be useful to researchers to test drugs that could help with symptoms of early stage Alzheimer’s disease,” Borchelt said.This research is funded by the National Institute of Neurological Disease and Stroke of the National Institutes of Health, and the SantaFe HealthCare Alzheimer’s Disease Research Center of the University of Florida.

Infant brains imply adult ills: Researchers study traits in babies as young as two weeks

Brain images from newborns are giving scientists a glimpse of the future - not just into the lives of their tiny subjects but also paths to treatment for adult patients with schizophrenia and Alzheimer’s disease.

Researchers from the University of North Carolina-Chapel Hill found degeneration in the brains of 2-week-old infants, a result considered a “game changer” for the field of brain research, said Jay Giedd, a brain imaging specialist for the National Institute of Mental Health.

"Our original model was that the brain was fine until someone got the illness," Giedd said. "This work shows that these changes are there probably from conception. It also suggests that while these traits don’t cause brain damage, they set up the brain to be slightly different."

The researchers examined scans of 272 newborns. About 15 percent were found to have smaller medial temporal lobe sections. “The medial temporal lobe plays an important role in memory,” said Rebecca Knickmeyer, a UNC assistant professor of psychiatry and co-author of the research, published last month in Cerebral Cortex, an online journal.

"The idea is that this is an anatomical vulnerability. If you start out with less, you might hit active symptoms earlier in life."

The researchers also found specific gene traits associated with Alzheimer’s in babies with the smaller media temporal lobes.

"We were interested because it was generally known that people’s genes contribute to psychiatric conditions later in life, but pretty much all the existing studies were in adults," Knickmeyer said. "Our question was ‘When were these genes exerting their effect?’ Now we know it’s much earlier than previously thought, perhaps before birth."

Research such as this would benefit from the Brain Activity Map under development through the National Institutes of Health. The project’s 10-year goal is to create a map of the brain’s nearly 30,000 genes as well as the circuitry system that transmits information via brain waves.

President Obama mentioned the project in his State of the Union address and is expected to include funding for the project in the upcoming federal budget. Foundations and some private companies have also expressed interest in assisting in the project, which is expected to push brain research to a higher level.

"As brain scientists, we were giddy to hear this," Giedd said. "Motivation is sky high. If they fund this, we believe our work will really take off." Giedd, who is familiar with but did not participate in the infant brain study, said the search for treatments or cures for diseases such as Alzheimer’s, autism, schizophrenia and Parkinson’s disease have been stymied by the many mysteries that remain regarding how the brain functions.

"If we understood more about the mechanisms that cause these diseases, we could step in and do something about it," Giedd said. "The brain is so complicated. Most diseases don’t just involve one or two or even three genes. It might be 60 or 100 genes, along with upbringing, diet and environment. There are so many parameters to the equation."

Knickmeyer said her research team plans to follow up with the newborns as they grow into adulthood to see whether the traits displayed by infants change over time or remain stable throughout their lives.

Daniel Kaufer, cognitive neurology and memory disorders chief for UNC’s Department of Neurology, said he thinks the time is right for great advances in brain research.

"We are at the crossroads of two important events: the realization that brain disorders may occur long before symptoms begin, and the development of brain imaging technology to record brain processes," Kaufer said.

Learning more about the brain’s functions through gene mapping may be the third piece of the puzzle. “Right now, there is no map of the human brain,” said Murali Doraiswamy, professor of psychiatry and behavioral sciences at Duke University School of Medicine.

Doraiswamy said the brain carries thousands of genes that influence thought, perception, emotion, memory and other mental activities. “We want to find out how much is nature and how much is nurture,” he added. “I think we are at the forefront of something very insightful, but also a little frightening.”

MAPPING A NEW WORLD

The Brain Activity Map is being planned as a decade-long research effort to create a comprehensive outline of the structure of the human brain and its neurons.

Funding is expected to come from a variety of sources, including the federal government, private industry and research foundations.

Details of the project have not yet been made public. But it is being compared to the DNA sequencing effort known as the Human Genome Project, which ran from 1990 to 2003 and cost $3.8 billion.

Scientists Find Way to Image Brain Waste Removal Process Which May Lead to Alzheimer’s Diagnostic

A novel way to image the entire brain’s glymphatic pathway, a dynamic process that clears waste and solutes from the brain that otherwise might build-up and contribute to the development of Alzheimer’s disease, may provide the basis for a new strategy to evaluate disease susceptibility, according to a research paper published online in The Journal of Clinical Investigation. Through contrast enhanced magnetic resonance imaging (MRI) and other tools, a Stony Brook University-led research team successfully mapped this brain-wide pathway and identified key anatomical clearance routes of brain waste.

In their article titled “Brain-wide pathway for waste clearance captured by contrast enhanced MRI,” Principal Investigator Helene Benveniste, MD, PhD, a Professor in the Departments of Anesthesiology and Radiology at Stony Brook University School of Medicine, and colleagues built upon a previous finding by Jeffrey Iliff, PhD, and Maiken Nedergaard, MD, PhD, from University of Rochester that initially discovered and defined the glymphatic pathway, where cerebral spinal fluid (CSF) filters through the brain and exchanges with interstitial fluid (ISF) to clear waste, similar to the way lymphatic vessels clear waste from other organs of the body. Despite the discovery of the glymphatic pathway, researchers could not visualize the brain wide flow of this pathway with previous imaging techniques.

“Our experiments showed proof of concept that the glymphatic pathway function can be measured using a simple and clinically relevant imaging technique,” said Dr. Benveniste. “This technique provides a three-dimensional view of the glymphatic pathway that captures movement of waste and solutes in real time. This will help us to define the role of the pathway in clearing matter such as amyloid beta and tau proteins, which affect brain processes if they build up.”

Dr. Benveniste said that the pathology of certain neurological conditions is associated with the accumulation of these proteins and other large extracellular aggregates. In particular, she explained that plaque deposits of these proteins are implicated in the development of Alzheimer’s disease, as well as chronic traumatic encephalopathy that occurs after repetitive mild traumatic brain injuries.

Modeling Alzheimer’s disease using iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness

Working with a group from Nagasaki University, a research group at the Center for iPS Cell Research and Application (CiRA) has successfully modeled Alzheimer’s disease (AD) using both familial and sporadic patient-derived induced pluripotent stem cells (iPSCs), and revealed stress phenotypes and differential drug responsiveness associated with intracellular amyloid β oligomers in AD neurons and astrocytes.

In a study published online in Cell Stem Cell, Associate Professor Haruhisa Inoue and his team at CiRA and a research group led by Professor Nobuhisa Iwata of Nagasaki University generated cortical neurons and astrocytes from iPSCs derived from two familial AD patients with mutations in amyloid precursor protein (APP), and two sporadic AD patients. The neural cells from one of the familial and one of the sporadic patients showed endoplasmic reticulum (ER)-stress and oxidative-stress phenotypes associated with intracellular Aβ oligomers. The team also found that these stress phenotypes were attenuated with docosahexaenoic acid (DHA) treatment. These findings may help explain the variable clinical results obtained using DHA treatment, and suggest that DHA may in fact be effective only for a subset of patients.
Using both familial and sporadic AD iPSCs, the researchers discovered that pathogenesis differed between individual AD patients. For example, secreted Aβ42 levels were depressed in familial AD with APP E693Δ mutation, elevated in familial AD with APP V717L mutation, but normal in sporadic AD.

"This shows that patient classification by iPSC technology may contribute to a preemptive therapeutic approach toward AD," said Inoue, a principal investigator at CiRA who is also a research director for the CREST research program funded by the Japan Science and Technology Agency. "Further advances in iPSC technology will be required before large-scale analysis of AD patient-specific iPSCs is possible."

Smoking damages mouse brains

Cigarette smoke damages the lungs, but it also wreaks havoc in the brain, a study in mice suggests. Signs of Alzheimer’s disease increased in the brains of animals that breathed cigarette smoke for four months, scientists report February 19 in Nature Communications.

The relationship between smoking and Alzheimer’s in people is murky. Some evidence from the 1990s suggested that smoking actually protected people against Alzheimer’s, presumably by stimulating nicotine-detecting brain cells. More recent studies have found that smoking ups the odds of the disease.

To see what cigarettes do to the brain, scientists led by Claudio Soto of the University of Texas Medical School at Houston turned to mice. In animals bred to show signs of Alzheimer’s, cigarette smoke (one cigarette’s worth in air the mouse breathed for an hour, five days a week) worsened aspects of the disease. Compared with mice that weren’t exposed, mice exposed to smoke had several signs of Alzheimer’s: they had more amyloid beta plaques, a higher load of abnormal tau protein and more severe inflammation in their brains.

The scientists don’t know yet how cigarette smoke causes these changes, or whether a similar process happens in people.

Scientists identify molecular system that could help develop potential treatments for conditions such as Alzheimer’s disease

Scientists from the University of Southampton have identified the molecular system that contributes to the harmful inflammatory reaction in the brain during neurodegenerative diseases.

An important aspect of chronic neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s or prion disease, is the generation of an innate inflammatory reaction within the brain.

Results from the study open new avenues for the regulation of the inflammatory reaction and provide new insights into the understanding of the biology of microglial cells, which play a leading role in the development and maintenance of this reaction.

Dr Diego Gomez-Nicola, from the CNS Inflammation group at the University of Southampton and lead author of the paper, says: “The understanding of microglial biology during neurodegenerative diseases is crucial for the development of potential therapeutic approaches to control the harmful inflammatory reaction. These potential interventions could modify or arrest neurodegenerative diseases like Alzheimer disease.

“The future potential outcomes of this line of research would be rapidly translated into the clinics of neuropathology, and would improve the quality of life of patients with these diseases.”

Microglial cells multiply during different neurodegenerative conditions, although little is known about to what extent this accounts for the expansion of the microglial population during the development of the disease or how it is regulated.

Writing in The Journal of Neuroscience, scientists from the University of Southampton describe how they used a laboratory model of neurodegeneration (murine prion disease), to understand the brain’s response to microglial proliferation and dissected the molecules regulating this process. They found that signalling through a receptor called CSF1R is a key for the expansion of the microglial population and therefore drugs could target this.

Dr Diego Gomez-Nicola adds: “We have been able to identify that this molecular system is active in human Alzheimer’s disease and variant Creutzfeldt–Jakob disease, pointing to this mechanism being universal for controlling microglial proliferation during neurodegeneration. By means of targeting CSF1R with selective inhibitors we have been able to delay the clinical symptoms of experimental prion disease, also preventing the loss of neurons.”