Posts tagged neurodegeneration
Articles and news from the latest research reports.
(Image caption: In the top image, cells from a mouse model of amyotrophic lateral sclerosis caused normal healthy brain cells (green) to die. But when scientists blocked an enzyme in the cells from the mouse model, more of the normal cells and their branches survived (bottom))
Digoxin, a medication used in the treatment of heart failure, may be adaptable for the treatment of amyotrophic lateral sclerosis (ALS), a progressive, paralyzing disease, suggests new research at Washington University School of Medicine in St. Louis.
ALS, also known as Lou Gehrig’s disease, destroys the nerve cells that control muscles. This leads to loss of mobility, difficulty breathing and swallowing and eventually death. Riluzole, the sole medication approved to treat the disease, has only marginal benefits in patients.
But in a new study conducted in cell cultures and in mice, scientists showed that when they reduced the activity of an enzyme or limited cells’ ability to make copies of the enzyme, the disease’s destruction of nerve cells stopped. The enzyme maintains the proper balance of sodium and potassium in cells.
“We blocked the enzyme with digoxin,” said senior author Azad Bonni, MD, PhD. “This had a very strong effect, preventing the death of nerve cells that are normally killed in a cell culture model of ALS.”
The findings appear online Oct. 26 in Nature Neuroscience.
The results stemmed from Bonni’s studies of brain cells’ stress responses in a mouse model of ALS. The mice have a mutated version of a gene that causes an inherited form of the disease and develop many of the same symptoms seen in humans with ALS, including paralysis and death.
Efforts to monitor the activity of a stress response protein in the mice unexpectedly led the scientists to another protein: sodium-potassium ATPase. This enzyme ejects charged sodium particles from cells and takes in charged potassium particles, allowing cells to maintain an electrical charge across their outer membranes.
Maintenance of this charge is essential for the normal function of cells. The particular sodium-potassium ATPase highlighted by Bonni’s studies is found in nervous system cells called astrocytes. In the ALS mice, levels of the enzyme are higher than normal in astrocytes.
Bonni’s group found that the increase in sodium-potassium ATPase led the astrocytes to release harmful factors called inflammatory cytokines, which may kill motor neurons.
Recent studies have suggested that astrocytes may be crucial contributors to neurodegenerative disorders such as ALS, and Alzheimer’s, Huntington’s and Parkinson’s diseases. For example, placing astrocytes from ALS mice in culture dishes with healthy motor neurons causes the neurons to degenerate and die.
“Even though the neurons are normal, there’s something going on in the astrocytes that is harming the neurons,” said Bonni, the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology.
How this happens isn’t clear, but Bonni’s results suggest the sodium-potassium ATPase plays a key role. When he conducted the same experiment but blocked the enzyme in ALS astrocytes using digoxin, the normal motor nerve cells survived. Digoxin blocks the ability of sodium-potassium ATPase to eject sodium and bring in potassium.
In mice with the mutation for inherited ALS, those with only one copy of the gene for sodium-potassium ATPase survived an average of 20 days longer than those with two copies of the gene. When one copy of the gene is gone, cells make less of the enzyme.
“The mice with only one copy of the sodium-potassium ATPase gene live longer and are more mobile,” Bonni said. “They’re not normal, but they can walk around and have more motor neurons in their spinal cords.”
Many important questions remain about whether and how inhibitors of the sodium-potassium ATPase enzyme might be used to slow progressive paralysis in ALS, but Bonni said the findings offer an exciting starting point for further studies.
Fixing a faulty molecular ‘transport hub’ could slow brain degeneration
University of Queensland researchers have gained new insights into how the body sorts and transports protein ‘cargo’ within our cells, in a finding that could eventually lead to treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
An international research team co-led by Dr Brett Collins from UQ’s Institute for Molecular Bioscience has revealed the structure of a molecular transport hub that sorts, directs and transports protein to correct destinations in the cell.
Dr Collins said protein cargoes that failed to reach the correct destinations in cells created ‘traffic jams’ that could affect neuronal activity and brain function.
“Having an understanding of how these proteins work together to sort and transport cargo could be the first step in developing drugs that reverse the effects of toxic protein accumulation in neurodegenerative disease,” he said.
Dr Collins has been studying how cargo is sorted, packaged, and trafficked within human cells for more than a decade.
He said that developing drugs that fix faulty proteins such as the transport hub was a relatively new and exciting approach to treatment.
“Traditionally, drugs are developed to try to block or inhibit the function of proteins in the body,” Dr Collins said.
“The problem with drugs that completely stop the function of a protein is that you often get harmful side-effects.”
Dr Collins said the promising finding provided new avenues to target multiple parts of the transport hub to enhance its function by stabilising the protein.
“If we can enhance or improve the function of this protein we could potentially slow down the brain degeneration that occurs in diseases such as Alzheimer’s and Parkinson’s,” he said.
(Source: uq.edu.au)
Compound protects brain cells after traumatic brain injury
A new class of compounds has now been shown to protect brain cells from the type of damage caused by blast-mediated traumatic brain injury (TBI). Mice that were treated with these compounds 24-36 hours after experiencing TBI from a blast injury were protected from the harmful effects of TBI, including problems with learning, memory, and movement.
Traumatic brain injury caused by blast injury has emerged as a common health problem among U.S. servicemen and women, with an estimated 10 to 20 percent of the more than 2 million U.S. soldiers deployed in Iraq or Afghanistan having experienced TBI. The condition is associated with many neurological complications, including cognitive and motor decline, as well as acquisition of psychiatric symptoms like anxiety and depression, and brain tissue abnormalities that resemble Alzheimer’s disease.
"The lack of neuroprotective treatments for traumatic brain injury is a serious problem in our society," says Andrew Pieper, senior study author and associate professor of psychiatry, neurology, and radiation oncology at the University of Iowa Carver College of Medicine. “Everyone involved in this work is motivated to find a way to offer hope for patients, which today include both military personnel and civilians, by establishing a basis for a new treatment to combat the deleterious neuropsychiatric outcomes after blast injury.”
It is known that TBI, as well as certain neurodegenerative diseases, damages axons—the tendril-like fibers that sprout from brains cells (neurons) and form the connections called synapses. In TBI, axon damage is followed by death of the neuron. The new study, published Sept. 11 in the journal Cell Reports, shows that a group of compounds, called the P7C3 series, blocks axon damage and preserves normal brain function following TBI.
Pieper led the team of scientists that discovered the P7C3 compound several years ago at UT Southwestern Medical Center. Subsequent studies showed that the root compound and its active analogs protect newborn neurons from cell death and also protect mature neurons in animal models of neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS).
The researchers have also previously shown efficacy of P7C3 molecules in brain injury due to concussion, and plan to investigate whether these compounds might be applicable in stroke as well, given that there appear to be common factors mediating neuronal cell death in these conditions.
By tweaking the structure of the original P7C3 compound, Pieper and his colleagues Joseph Ready and Steven McKnight, at UT Southwestern Medical Center, have further improved its potency and drug-like properties. In the latest study, Pieper’s team at the UI Carver College of Medicine, including co-first authors graduate student Terry Yin, senior technician Jeremy Britt, and graduate student Hector De Jesus-Cortes, tested the neuroprotective effects of the newest version, (-)-P7C3-S243, which can be given orally, in mice with blast-induced TBI.
In the study, blast-induced TBI caused learning, memory, and movement problems in the mice, which resemble the problems experienced by people affected by TBI. The researchers found that (-)-P7C3-S243 prevented acute memory and learning impairment caused by TBI. The compound also prevented TBI-associated balance and coordination problems in mice exposed to blast-injury. By examining the brain tissue at a cellular level, the team also found that the protection afforded to brain functions after injury was matched by preservation of normal neuronal axon structure and synaptic neurotransmission.
Importantly, the compound still produced its protective effects even when treatment was delayed until 24 to 36 hours after the blast injury.
"Seeing protection even when the compound was given this long after injury was important because it represents a liberal window of time within which almost all patients would be expected to be able to access treatment after injury," Pieper says.
The team also found that learning, memory, and coordination problems caused by the TBI persisted in untreated mice at least eight months after the single injury occurred, suggesting that the compound actually prevented these problems rather simply speeding up a normal recovery process.
In a separate study led by Pieper’s colleagues McKnight and Ready at UT Southwestern, and also published on Sept. 11 in the journal Cell, the team has identified the biological mechanism by which P7C3 compounds act in the brain. The compounds activate the molecular pathway that preserves neuronal levels of an energy molecule known as nicotinamide adenine dinucleotide (NAD).
"Based on the well-established role of NAD in axonal degeneration, the ability of (-)-P7C3-S243 to protect mice after blast-mediated traumatic brain injury is likely related to preservation of NAD levels," Pieper explains. "Now that we understand the mechanism of action of the P7C3 class of compounds, we can see why they should have therapeutic utility in an unusually broad spectrum of neurodegenerative conditions, without impeding any of a number of other normal forms of cell death.
"Our ultimate goal is to facilitate development of a new class of neuroprotective drugs with wide applicability to treating patients with TBI and other currently untreatable forms of neurodegeneration," he adds.
Study Finds Air Pollution Harmful to Young Brains
Pollution in many cities threatens the brain development in children.
Findings by University of Montana Professor Dr. Lilian Calderón-Garcidueñas, MA, MD, Ph.D., and her team of researchers reveal that children living in megacities are at increased risk for brain inflammation and neurodegenerative changes, including Alzheimer’s or Parkinson’s disease.
Calderón-Garcidueñas’ findings are detailed in a paper titled “Air pollution and children: Neural and tight junction antibodies and combustion metals, the role of barrier breakdown and brain immunity in neurodegeneration,” which can be found online at http://iospress.metapress.com/content/xx6582688105j48h/.
The study found when air particulate matter and their components such as metals are inhaled or swallowed, they pass through damaged barriers, including respiratory, gastrointestinal and the blood-brain barriers and can result in long-lasting harmful effects.
Calderón-Garcidueñas and her team compared 58 serum and cerebrospinal fluid samples from a control group living in a low-pollution city and matched them by age, gender, socioeconomic status, education and education levels achieved by their parents to 81 children living in Mexico City.
The results found that the children living in Mexico City had significantly higher serum and cerebrospinal fluid levels of autoantibodies against key tight-junction and neural proteins, as well as combustion-related metals.
“We asked why a clinically healthy kid is making autoantibodies against their own brain components,” Calderón-Garcidueñas said. “That is indicative of damage to barriers that keep antigens and neurotoxins away from the brain. Brain autoantibodies are one of the features in the brains of people who have neuroinflammatory diseases like multiple sclerosis.”
The issue is important and relevant for one reason, she explained. The breakdown of the blood-brain barrier and the presence of autoantibodies to important brain proteins will contribute to the neuroinflammation observed in urban children and raises the question of what role air pollution plays in a 400 percent increase of MS cases in Mexico City, making it one of the main diagnoses for neurology referrals.
Calderón-Garcidueñas points out that there is a need for a longitudinal follow-up study to determine if there is a relationship between the cognition deficits and brain MRI alterations previously reported in Mexico City children, and their autoimmune responses. But what is clear is that the kids are suffering from immune dysregulation.
Once there is a breakdown in the blood-brain barrier, not only will particulate matter enter the body but it also opens the door to harmful neurotoxins, bacteria and viruses.
“The barriers are there for a reason,” she explains. “They are there to protect you, but once they are broken the expected results are not good.”
The results of constant exposure to air pollution and the constant damage to all barriers eventually result in significant consequences later in life. She explains that the autoimmune responses are potentially contributing to the neuroinflammatory and Alzheimer’s and Parkinson’s pathology they are observing in young urban children.
While the study focused on children living in Mexico City, others living in cities where there are alarming levels of air pollution such as Los Angeles, Philadelphia-Wilmington, New York City, Salt Lake City, Chicago, Tokyo, Mumbai, New Delhi or Shanghai, among others, also face major health risks. In the U.S. alone, 200 million people live in areas where pollutants such as ozone and fine particulate matter exceed the standards.
“Investing in defining the central nervous system pathology associated with exposure to air pollutants in children is of pressing importance for public health,” Calderón-Garcidueñas said.
The full article is scheduled to be published in Volume 43, Issue 3 of the Journal of Alzheimer’s Disease and will appear online at http://www.j-alz.com in December with a 2015 copyright.
(Source: news.umt.edu)
Broken signals lead to neurodegeneration
Researchers from the RIKEN Brain Science Institute in Japan, in collaboration with Juntendo University and the Japan Science and Technology Agency, have discovered that a cell receptor widely involved in intracellular calcium signaling—the IP3R receptor—can be locked into a closed state by enzyme action, and that this locking may potentially play a role in the reduction of neuron signaling seen in neurodegenerative diseases such as Huntington’s and Alzheimer’s disease.
In the research published today in the Proceedings of the National Academy of Sciences, the scientists reported experiments in human cells and a mouse model of Huntington’s disease revealing that transglutaminase type 2—a protein cross-linking enzyme elevated in the cells of patients with neurodegenerative diseases—interacts with the IP3R receptor to lock it in a closed non-functional conformation preventing it from fulfilling its essential calcium-releasing role. They identified a specific amino acid site on the receptor, Gln2746, where the modification takes place, deepening our understanding of how receptors are locked and potentially opening the door to studies on other functional proteins that are also regulated by conformational changes.
The IP3R channel, which is located in the endoplasmic reticulum, a protein assembly and transport compartment, plays a crucial role in intracellular calcium signaling, and is involved in a wide range of cell functions including mitochondrial energy production and the regulation of autophagy, the process through which cells consume and degrade unused components to maintain a healthy balance of functional proteins. Although autophagy is normally a mechanism that sustains cell maintenance, it can also trigger a loss of cell function and has been associated with prominent diseases including Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease.
In this work, the scientists propose a general model under which abnormal IP3R-mediated calcium signaling caused by the action of transglutaminase type 2 leads to cellular dysfunction and subsequently to the emergence of progressive brain dysfunction. Transglutaminase 2 activation is commonly associated with inflammation and stress, and its action on the IP3R channel might provide an explanation for the initiation and progression steps common to different neurodegenerative diseases.
According to Katsuhiko Mikoshiba, who led the study, “We think that the mechanism we identified in this study could provide us with a more general model of other diseases both of the brain and other parts of the body, where transglutaminase type 2 is upregulated. We hope that this insight could eventually lead to the development of new drug therapies for a number of neurodegenerative diseases that place a high burden on patients and society.”
Why HIV patients develop dementia
Immune cells in the brain under suspicion
“HIV-associated neurocognitive disorders” (HAND) include disorders of the cognitive functions, motor capacities as well as behavioural changes. How exactly HAND occur has not, as yet, been fully understood. “Scientists assume that HIV is harmful to cells directly and that it also triggers indirect mechanisms that lead to nerve cell damage,” explains Dr Simon Faissner (RUB clinic for neurology, St. Josef-Hospital). The researchers strongly suspect that, once activated in the brain and the spinal cord, immune cells keep up a chronic inflammation level which then results in the destruction of nerve cells. An immune activation in peripheral tissue as well as therapeutic consequences may likewise contribute to nerve cell damage in the brain.
First steps of HIV infection are sufficient
The HI virus overcomes the blood-brain barrier hitchhiking on infected immune cells, the monocytes and probably the T cells. The researchers from Bochum tested the hypothesis that HIV-infected monocytes activate specific immune cells in the brain, the so-called microglial cells. These cells, in turn, respond by releasing harmful substances, such as reactive oxygen metabolites and inflammatory signalling molecules, i.e. cytokines. To test this hypothesis, the researchers developed a cell culture system in which they initially examined the effect of HIV-infected monocytes on microglial cells. The researchers simulated the individual steps of HIV infection and measured the concentration of the cytokines released at each stage. Thus, they were able to demonstrate that releasing the viral RNA in the monocytes was a sufficient trigger for maximal microglial activation. Subsequent infection phases – reverse transcription into DNA and the resulting formation of HIV proteins – did not augment activation any further.
Released substances result in neuronal cell death
In the second step, they analysed nerve cells from rat brains to determine if the substances released by the microglial cells could lead to cell death. Compared with the control group, the amount of cell death was indeed twice as high. Studies of liquor cerebrospinalis received from HIV-infected patients have shown a positive correlation with marker of neuronal degeneration in patients who did not as yet present any neurocognitive disorders.
Detailed understanding necessary for therapeutic strategies
“Thanks to our research, we have gained a better understanding of the mechanisms of HIV-associated neurodegeneration,” concludes Prof Dr Andrew Chan. “These results are likely to contribute to HAND biomarkers becoming established. In the long term, these data may be used to develop therapeutic strategies aiming at retarding HAND progression in HIV-infected patients.” Starting points may include activation of microglial cells – a method that is applied in other autoimmune diseases of the central nervous system, for example in multiple sclerosis.
Start-up through FoRUM funds
The research, which was initiated following a collaboration between clinics for neurology and dermatology, St. Josef Hospital, as well as the Department for Molecular and Medical Virology, has been made possible through start-up funding provided by the Faculty of Medicine at Ruhr-Universität (FoRUM). The collaboration has evolved into an international consortium of clinics and basic research organisations in Bochum, Langen, Strasbourg and Mailand. One objective of the follow-up study, for which an application for EU funds is pending, is going to be an in-depth analysis of inflammatory processes in the central nervous system. The researchers will attempt to inhibit inflammatory processes with different drugs. They are, moreover, planning to study direct cell-cell interaction by means of state-of-the-art microscopy, in collaboration with the University of Strasbourg.
(Image credit: Mehau Kulyk/Science Photo Library)
New technique could benefit Alzheimer’s diagnosis
Swinburne researchers have developed a technique to create a highly sensitive surface for measuring the concentration of a peptide that is a biomarker for early stage Alzheimer’s disease.
(Image caption: Ultrashort-laser pulses were used to write ripples on the surface of sapphire. The self-organised nano-structure of ripples (seen in the image) is a perfect sensing surface after coating with a nanometre-thin layer of gold made by evaporation or sputtering. Such surface ripples were used in the study of amyloid detection.)
Alzheimer’s disease was first recorded more than 100 years ago, but there is still no effective therapy to stop or slow the progression of the disease. Sufferers can lose up to 60 per cent of their neuronal cells before a diagnosis is obtained.
Diagnosis at the very early stages before neuronal degeneration has begun is vital for testing and developing new treatments.
Abnormality of the beta amyloid peptide in cerebrospinal fluid appears to be the earliest and most significant marker of Alzheimer’s. Currently there are no standardised tests to detect these biomarkers.
The researchers have developed a sensor based on nanotechnology that outperforms commercial sensors and demonstrates fast and reliable measurement of beta amyloid oligomers at low concentrations.
The key to the high sensitivity is the laser nano-textured gold coated surface. This sensor can identify concentrations of beta amyloid in a quantitative manner for the first time.
“We showed that sensors based on light scattering can indeed deliver QUANTATIVE measurements and they can be made fast,” Professor of Nanophotonics Saulius Juodkazis said.
“The sensor platform we developed by laser nano-texturing of surfaces is delivering results of the highest sensitivity and repeatability.
“The challenge is to create fast and efficient fabrication of sensors based on nanotechnology and develop new analytical methods of detection. This means we should be able to detect markers of diseases at far lower levels.”
Surface enhanced Raman spectroscopy (SERS) is one of the most sensitive and highly specific label-free detection methods which may evolve as a detection technique for different forms of beta amyloid or as a rapid, low cost technique to validate new biomarkers before developing standard assays for enzyme-linked immunosorbent assays (ELISAs).
This research is a PhD project work of Dr Ricardas Buividas who received his doctorate in May 2014. It was published in the Journal of Biophotonics.
(Source: swinburne.edu.au)
Marijuana compound may offer treatment for Alzheimer’s disease
Extremely low levels of the compound in marijuana known as delta-9-tetrahydrocannabinol, or THC, may slow or halt the progression of Alzheimer’s disease, a recent study from neuroscientists at the University of South Florida shows.
Findings from the experiments, using a cellular model of Alzheimer’s disease, were reported online in the Journal of Alzheimer’s Disease.
Researchers from the USF Health Byrd Alzheimer’s Institute showed that extremely low doses of THC reduce the production of amyloid beta, found in a soluble form in most aging brains, and prevent abnormal accumulation of this protein — a process considered one of the pathological hallmarks evident early in the memory-robbing disease. These low concentrations of THC also selectively enhanced mitochondrial function, which is needed to help supply energy, transmit signals, and maintain a healthy brain.
“THC is known to be a potent antioxidant with neuroprotective properties, but this is the first report that the compound directly affects Alzheimer’s pathology by decreasing amyloid beta levels, inhibiting its aggregation, and enhancing mitochondrial function,” said study lead author Chuanhai Cao, PhD and a neuroscientist at the Byrd Alzheimer’s Institute and the USF College of Pharmacy.
“Decreased levels of amyloid beta means less aggregation, which may protect against the progression of Alzheimer’s disease. Since THC is a natural and relatively safe amyloid inhibitor, THC or its analogs may help us develop an effective treatment in the future.”
The researchers point out that at the low doses studied, the therapeutic benefits of THC appear to prevail over the associated risks of THC toxicity and memory impairment.
Neel Nabar, a study co-author and MD/PhD candidate, recognized the rapidly changing political climate surrounding the debate over medical marijuana.
“While we are still far from a consensus, this study indicates that THC and THC-related compounds may be of therapeutic value in Alzheimer’s disease,” Nabar said. “Are we advocating that people use illicit drugs to prevent the disease? No. It’s important to keep in mind that just because a drug may be effective doesn’t mean it can be safely used by anyone. However, these findings may lead to the development of related compounds that are safe, legal, and useful in the treatment of Alzheimer’s disease.”
The body’s own system of cannabinoid receptors interacts with naturally-occurring cannabinoid molecules, and these molecules function similarly to the THC isolated from the cannabis (marijuana) plant.
Dr. Cao’s laboratory at the Byrd Alzheimer’s Institute is currently investigating the effects of a drug cocktail that includes THC, caffeine as well as other natural compounds in a cellular model of Alzheimer’s disease, and will advance to a genetically-engineered mouse model of Alzheimer’s shortly.
“The dose and target population are critically important for any drug, so careful monitoring and control of drug levels in the blood and system are very important for therapeutic use, especially for a compound such as THC,” Dr. Cao said.
Changes in the eye can predict changes in the brain
Researchers at the Gladstone Institutes and University of California, San Francisco have shown that a loss of cells in the retina is one of the earliest signs of frontotemporal dementia (FTD) in people with a genetic risk for the disorder—even before any changes appear in their behavior.
Published today in the Journal of Experimental Medicine, the researchers, led by Gladstone investigator Li Gan, PhD and UCSF associate professor of neurology Ari Green, MD, studied a group of individuals who had a certain genetic mutation that is known to result in FTD. They discovered that before any cognitive signs of dementia were present, these individuals showed a significant thinning of the retina compared with people who did not have the gene mutation.
“This finding suggests that the retina acts as a type of ‘window to the brain,’” said Dr. Gan. “Retinal degeneration was detectable in mutation carriers prior to the onset of cognitive symptoms, establishing retinal thinning as one of the earliest observable signs of familial FTD. This means that retinal thinning could be an easily measured outcome for clinical trials.”
Although it is located in the eye, the retina is made up of neurons with direct connections to the brain. This means that studying the retina is one of the easiest and most accessible ways to examine and track changes in neurons.
Lead author Michael Ward, MD, PhD, a postdoctoral fellow at the Gladstone Institutes and assistant professor of neurology at UCSF, explained, “The retina may be used as a model to study the development of FTD in neurons. If we follow these patients over time, we may be able to correlate a decline in retinal thickness with disease progression. In addition, we may be able to track the effectiveness of a treatment through a simple eye examination.”
The researchers also discovered new mechanisms by which cell death occurs in FTD. As with most complex neurological disorders, there are several changes in the brain that contribute to the development of FTD. In the inherited form researched in the current study, this includes a deficiency of the protein progranulin, which is tied to the mislocalization of another crucial protein, TDP-43, from the nucleus of the cell out to the cytoplasm.
However, the relationship between neurodegeneration, progranulin, and TDP-43 was previously unclear. In follow-up studies using a genetic mouse model of FTD, the scientists were able to investigate this connection for the first time in neurons from the retina. They identified a depletion of TDP-43 from the cell nuclei before any signs of neurodegeneration occurred, signifying that this loss may be a direct cause of the cell death associated with FTD.
TDP-43 levels were shown to be regulated by a third cellular protein called Ran. By increasing expression of Ran, the researchers were able to elevate TDP-43 levels in the nucleus of progranulin-deficient neurons and prevent their death.
“With these findings,” said Dr. Gan, “we now not only know that retinal thinning can act as a pre-symptomatic marker of dementia, but we’ve also gained an understanding into the underlying mechanisms of frontotemporal dementia that could potentially lead to novel therapeutic targets.”
(Source: gladstoneinstitutes.org)
Epigenetic breakthrough bolsters understanding of Alzheimer’s disease
A team led by researchers at the University of Exeter Medical School and King’s College London has uncovered some of the strongest evidence yet that epigenetic changes in the brain play a role in Alzheimer’s disease.
Epigenetic changes affect the expression or activity of genes without changing the underlying DNA sequence and are believed to be one mechanism by which the environment can interact with the genome. Importantly, epigenetic changes are potentially reversible and may therefore provide targets for the development of new therapies.
Globally, more than 26 million people are currently affected by Alzheimer’s Disease. As this number grows in line with an increasingly aging population, the need to identify new disease mechanisms is more important than ever. Post-mortem examinations have revealed much about how Alzheimer’s damages the brain, with some regions, such as the entorhinal cortex, being particularly susceptible, while others, such as the cerebellum, remain virtually unscathed. However, little is yet known about how and why the disease develops in specific brain regions.
The current study found that chemical modifications to DNA within the ANK1 gene are strongly associated with measures of neuropathology in the brain. The study, published in Nature Neuroscience, found that people with more Alzheimer’s disease-related neuropathology in their brains had higher levels of DNA modifications within the ANK1 gene. The finding was particularly strong in the entorhinal cortex, and also detected in other cortical regions affected by the disease. In contrast, no significant changes were observed in less affected brain regions or blood.
Professor Jonathan Mill, of the University of Exeter Medical School and King’s College London, who headed the study, said: “This is the strongest evidence yet to suggest that epigenetic changes in the brain occur in Alzheimer’s disease, and offers potential hope for understanding the mechanisms involved in the onset of dementia. We don’t yet know why these changes occur – it’s possible that they are involved in disease onset, but they may also reflect changes induced by the disease itself.”
Dr Katie Lunnon, first author on the study, from the University of Exeter Medical School, added: “It’s intriguing that we find changes specifically in the regions of the brain involved in Alzheimer’s disease. Future studies will focus on isolating different cell-types from the brain to see whether these changes are neuron-specific.”
In addition to the University of Exeter Medical School and King’s College London, the team included contributors from The Icahn School of Medicine at Mount Sinai, the JJ Peters VA Medical Center, The Johns Hopkins University School of Medicine, Harvard Medical School, the University of Oxford, and Rush University Medical Center, Chicago. They used cutting-edge technology to examine brain tissue from different areas of the brain across three cohorts - the MRC London Brain Bank for Neurodegenerative Disease, the Oxford Thomas Willis Brain Bank, and the Mount Sinai Alzheimer’s Disease and Schizophrenia Brain Bank. They analysed three cortical regions, cerebellum, and blood obtained from several hundred individuals representing the spectrum of disease; from those with no evidence of dementia and neurodegeneration, through to patients with very advanced disease.
The research was primarily funded by the National Institutes of Health (NIH), U.S. Department of Health and Human Services, as part of its Epigenomics Roadmap Initiative (grant number R01-AG036039 awarded to Jonathan Mill). To learn more about the NIH initiative that seeks to accelerate research into the relatively new and fast-developing area of epigenetics, go to: https://commonfund.nih.gov/epigenomics/index.
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, who also provided funding for the study said:“We know that changes to the DNA code of certain genes are associated with an increased risk of developing Alzheimer’s disease. Investigating how epigenetic changes influence genes in Alzheimer’s is still a relatively new area of study. The importance of understanding this area of research is highlighted by the fact that epigenetic changes have been associated with development of other diseases, including cancer.
“This innovative research has discovered a potential new mechanism involved in Alzheimer’s by linking the ANK1 gene to the disease. We will be interested to see further research into the role of ANK1 in Alzheimer’s and whether other epigenetic changes may be involved in the disease.
“Alzheimer’s affects millions of people worldwide and we need pioneering research to understand exactly why the disease occurs. Alzheimer’s Research UK is helping to fund research which will take us a step closer to understanding and defeating this devastating disease.”
(Source: exeter.ac.uk)