July 27, 2012 § Leave a comment
Parkinson’s disease is an incurable, progressive neurodegenerative disorder that affects 1 million Americans, and between 50,000 and 60,000 new cases are found annually. It is the second most common neurodegenerative disease after Alzheimer’s. It results in slowness of movement, rigidity, and tremors. PD is known to instigate cell loss, which often results in mild to acute brain damage.
Lithium has long been the gold standard for treatment of bipolar disorder. Now scientists at the Buck Institute for Research on Aging have discovered through rodent experimentation that Lithium also profoundly prevents the toxic protein aggregation that causes PD-related brain damage. Researchers at the Buck Institute are now ready to move into the preclinical stage to determine the correct dosages for the drug.
According to the June 24th edition of the Journal of Neuroscience Research, Buck researchers are working towards a Phase II human clinical study, using Lithium in concurrence with customary PD therapy. Lead author, Professor Julie Anderson, Ph.D., explains, “The fact that Lithium’s safety profile in humans is well understood greatly reduces trial risk.” Anderson explains that Lithium has significant anti-aging effects in animals. She mentions that, in contrast to the neurodegenerative properties of conditions such as Huntington’s disease, Alzheimer’s disease, and Amyotrophical Lateral Sclerosis, Lithium has recently been suggested to be neuroprotective.
Although overuse of Lithium has been known to cause hyperthyroidism and kidney toxicity, low dosages of the drug were given to the mice used in the Buck experimentation. Anderson remarks, “The possibility that Lithium could be effective in PD patients at subclinical levels is exciting, because it would avoid many side effects associated at the higher dose range.”
Although the Buck Institute’s research is still pre-clinical, success in previous experiments regarding the use of Lithium in humans is a predictor of future success in the case of patients with PD. In fact, research shows that many PD patients are already using Lithium, “off label,” in conjunction with their normal PD treatment regime. Also, Lithium salt supplements are available in some health food stores.
The familiarity of Lithium provides a better chance for the Buck Institute’s exploration with the drug. As Anderson explains, Lithium’s popularity, “lowers a significant hurdle to getting it into the clinic.”
“Lithium Profoundly Prevents Brain Damage Associated with Parkinson’s Disease”. (June 24, 2011). Neuroscience News. February 15, 2012. http://neurosciencenews.com/lithium-prevents-brain-damage-parkinsons-disease/.
July 18, 2012 § Leave a comment
A study published in the February edition of the medical journal of the American Academy of Neurology called Neurology reveals that a diet deficient in omega-3 fatty acids may cause the brain to age more rapidly, as well as lose a decent portion of its memory and thinking abilities.
Omega-3 fatty acids include the nutrients called docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). They are typically found in fish, marine and plant oils, eggs, turkey, and some beans and grains.
The study involved 1,575 people free of dementia at an average age of 67 who underwent brain scans, tests to measure mental function, body mass and omega-3 fatty acid levels in their blood. Results showed that people with DHA levels in the bottom 25% had a lower brain volume than those with a higher DHA level. Also those with the lower levels of omega-3 fatty acid levels scored lower on tests for visual memory, and executive functions such as multi-tasking, abstract thinking, and problem solving.
The author of the study is Zaldy S. Tan, M.D., M.P.H., of the Eastern Center for Alzheimer’s Disease Research and the Division of Geriatrics, University of California in Los Angeles. He says, “People with lower blood levels of omega-3 fatty acids had lower brain volumes that were equivalent to about two years of structural brain aging.”
This study was funded by the Framingham Heart Study’s National Heart, Lung, and Blood Institute as well as the National Institute on Aging.
“Low Levels of Omega-3 Fatty Acids May Cause Memory Problems”. (February 28, 2012). Neuroscience News. March 4, 2012. http://neurosciencenews.com/omega-3-fatty-acids-low-levels-memory-problems/.
July 4, 2012 § Leave a comment
Alzheimer’s affects 5.4 million Americans. This number is expected to double every 20 years. Neuroscientists at MIT have discovered the culprit of memory impairment associated with Alzheimer’s disease. The findings were published in the February online edition of Nature, lead by author Johannes Gräff, postdoctoral at the Picower Institute.
The overproduction of a blockading enzyme in the brain of Alzheimer’s patients thwarts the formation of new memories. The enzyme is known as HDAC2. MIT researchers observed that by inhibiting the enzyme in mice, a reversal of the symptoms of Alzheimer’s occurs. The findings suggest that therapeutic drugs aimed at this enzyme could better treat the disease.
The leader of the research team is Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT. Tsai says that the enzyme inhibitors could achieve this goal, but that it could take up to 10 years to develop and test the drugs. However, she strongly advocates a program to develop the agents. She says, “The disease is so devastating and affects so many people, so I would encourage more people to think about this.”
HDACs are a group of 11 enzymes that regulate genes by modifying histones. Histones are proteins that DNA reels around, forming chromatin. Through a process called deacetylation, HDACs alter histones, causing the chromatin to tighten its DNA and histone spool, making it less likely for the genes in this region to be expressed. The HDAC inhibitors loosen the spools, allowing for DNA expression. Tsai explains, “With such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions.”
During the study, researchers discovered that mice with Alzheimer’s symptoms had an overabundance of HDAC2 in the hippocampus. This is the site of new memory formation. This enzyme was clinging to the genes implicated in synaptic plasticity – the brain’s capacity for strengthening and weakening connections between neurons, which is critical for memory formation. Afflicted mice had less expression in these genes, due to tightening effect of the high concentration of the HDAC2 enzymes.
Using a molecule called short hairpin RNA – the molecule that carried genetic instructions from DNA to the cell – researchers shut off the HDAC2 in the afflicted mice. Histone acetylation recommenced and genes responsible for synaptic plasticity and learning memory processes were able to express. Normal cognitive function was redeemed in the treated mice.
Beta-amyloid protein clearing drugs are the treatment option most commonly used. The results are modest at best. These proteins cluster in the brains of Alzheimer’s patients and this causes an interference with the cell receptors required for synaptic plasticity. This new study revealed that beta amyloid stimulates the production of the HDAC2 enzyme.
Tsai explains, “We think that once this epigenetic blockade of gene expression is in place, clearing beta amyloid may not be sufficient to restore the active configuration of the chromatin.” He says that the HDAC2 inhibitors could reverse the symptoms of Alzheimer’s even after the blockade is created.
Before the drug can be entered into clinical trials, many more tests and development steps must be taken. Tsai believes clinical trials could be as many as 5 years away and approval will take as many as 10 years. To treat Alzheimer’s, the process of testing inhibitors must be extremely selective and precise.
“Reversing Alzheimer’s Gene Blockade Can Restore Memory, Other Cognitive Functions”. (February 29, 2012). Neuroscience News. March 3, 2012. http://neurosciencenews.com/reversing-alzheimers-gene-blockade-restores-memory-function/.
May 4, 2012 § Leave a comment
The disease is caused by anomalous deposits of the Amyloid-ß protein, which leads to a loss of synaptic connection between synapses. Recently, researchers have found an antibody that blocks this synaptic disintegration. This is good news for Alzheimer’s patients, as it may mean they will be able to fend off early cognitive decline associated with the disease.
In an article published March 7th in the Journal of Neuroscience, scientists at UCL have discovered antibodies that block the protein Dkk1, suppressing the toxicity of Amyloid-ß. Leading the study was professor of UCL Department of Cell and Development Biology Patricia Salinas. She said, “These novel findings raise the possibility that targeting this secreted Dkk1 protein could offer an effective treatment to protect synapses against the toxic effect of Amyloid-ß. Importantly, these results raise the hope for a treatment and perhaps the prevention of cognitive decline early in Alzheimer’s disease.”
In the brains of those with Alzheimer’s, elevated levels of Dkk1 are found. The research team at UCL has uncovered the significance of this. Amyloid-ß causes production of Dkk1. This protein dismantles synapses in the hippocampus, the area of the brain responsible for learning and memory.
The team conducted experiments on mice to observe the progression of synaptic disintegration in the event of Amyloid-ß exposure by using brain slices. They compared these to models who had been administered the antibody to see how many synapses survived. The results revealed that neurons exposed to the antibody remained healthy. Professor Salinas commented, “This research identifies Dkk1 as a potential therapeutic target for the treatment of Alzheimer’s disease.”
Dr. Simon Ridley, head of Research at Alzheimer’s Research UK, said, “By understanding what happens in the brain during Alzheimer’s, we stand a better chance of developing new treatments that could make a real difference to people with the disease. Studies like this are an essential part of that process, but more work is needed if we are to take these results from the lab bench to the clinic. Dementia can only be defeated through research, and with the numbers of people affected by the condition soaring, we urgently need to invest in research now.” Dr. Ridley’s advice will be followed in the coming months, as the body of research into the treatment and prevention of Alzheimer’s continues to grow.
“Specific Antibodies Halt Alzheimer’s Disease in Mice”. (March 7, 2012). Neuroscience News. March 8, 2012. http://neurosciencenews.com/antibodies-halt-alzheimers-disease-mice-dkk1/.
May 4, 2012 § 1 Comment
A study published in the March 6th issue of the Journal of Alzheimer’s Disease reveals that vitamin D3 might stimulate the immune system to clean out the brain plaques associated with Alzheimer’s disease. This vitamin regulates intracellular mechanisms, including ones that trigger cell-signaling networks that arouse the immune system to clear the brain of amyloid beta – the constituent of Alzheimer’s related brain plaques.
After previous laboratory work revealed that specific types of immune cells in Alzheimer’s patients respond to vitamin D3 and curcumin – a chemical found in turmeric spice – by prompting the immune system to clear the amyloid beta, researchers were intrigued. They just needed to find out how this happened.
For this recent study, researchers took blood samples from both Alzheimer’s patients and healthy individuals. They drew macrophages from each sample. These are immune cells that devour waste material such as the amyloid beta. These macrophages were then incubated with the amyloid beta. 1a,25-dihydroxyvitamin D3, a form of vitamin D3 produced in a conversion process within the liver and kidneys, was added to a few of the cells to test the effect it had on the amyloid beta assimilation.
A previous study of Alzheimer’s patients’ macrophages revealed two different types of patients and macrophages. They are divided into Type I, which are improved by the addition of 1a,25–dihydroxyvitamin D3 and curcuminoids, and Type II, which are improved only by the addition of 1a,25–dihydroxyvitamin D3. Both types of macrophages benefited from the addition of 1a,25–dihydroxyvitamin D3 because it opened up chloride channel 3 (CLC3), the chloride channel responsible for the phagocytosis (uptake) of the amyloid beta. This channel was only activated by curcuminoids in Type I macrophages. Researchers also found that the 1a,25–dihydroxyvitamin D3 helped generate the genetic transcription of itself, leading to gene expression.
In a partnership between Dr. Patrick R. Griffin of the Scripps Research Institute and Dr. Mathew T. Mizwicki, assistant research biochemist of UC Riverside, the effects of 1a,25–dihydroxyvitamin D3 were demonstrated through a technique based on mass spectrometry. It revealed that 1a,25–dihydroxyvitamin D3 provided more stability to the vitamin D receptor than the curcuminoids.
Mizwicki, the study’s main author, said, “Our findings demonstrate that active forms of vitamin D3 may be an important regulator of immune activities of macrophages in helping to clear amyloid plaques by directly regulating the expression of genes, as well as the structural physical workings of the cells.”
This study has helped clarify some key mechanisms that will help doctors and scientists better understand the value of vitamin D3 and curcumin as possible therapies for Alzheimer’s patients. Although it is too early to recommend vitamin D3 as a therapy, according to the research team, the next stage of their research will involve clinical trials to validate its dispensation for the treatment of the cognitive decline associated with Alzheimer’s disease.
“Scientists Pinpoint How Vitamin D May Help Clear Amyloid Plaques Found in Alzheimer’s Disease”. (March 6, 2012). Neuroscience News. March 9, 2012. http://neurosciencenews.com/vitamin-d-curcuminclear-amyloid-plaques-alzheimers-disease/.
May 4, 2012 § Leave a comment
A report published in the March 2 issue of Cell reveals a finding that may link microRNAs to memory and the learning process in general. Scientists at the John Hopkins University School of Medicine studied genetic material that controls protein formation in the brain and found that certain microRNAs control the actions of brain-derived neurotrophic factor (BDNF), which are linked to brain cell survival, learning, and memory boosting. These findings implicate that the use of a drug meant to enhance this function may prevent the mental illness that results from brain wasting diseases such as Huntington’s, Alzheimer’s, and Parkinson’s disease.
BDNF, a growth-factor protein, is released in the hippocampus during the learning process. This protein increases the activity of other proteins involved in memory formation, but only increases production of less than 4% of the brain cell proteins. Mollie K. Meffert, M.D., Ph.D., associate professor of biological chemistry and neuroscience at John Hopkins was determined to find out how BDNF decides which proteins to stimulate, and what is the role of the regulatory microRNAs – small molecules that block protein blueprint messages from being transferred to proteins by binding to them. Too many of these within a cell will halt protein production. Likewise, a loss of certain microRNAs will cause a higher production of proteins.
The researchers compared microRNA levels in the brain cells treated with BDNF to those left untreated. The former had lower levels of microRNAs, suggesting that BDNF controls the levels of these microRNAs, in turn affecting protein production. The microRNAs that were disappearing in the presence of BDNF were all Let-7 microRNAs.
The team then genetically engineered neurons that would stop decreasing Let-7 microRNAs to see if the loss of Let-7 microRNAs would cause BDNF to increase production of proteins. Treating the neurons with the BDNF no longer resulted in decreased microRNA levels (or increased learning and memory proteins). The researchers also found more than 174 microRNAs that increased due to the BDNF therapy, suggesting it may also increase other microRNAs, possibly decreasing the production of proteins that need to be decreased in learning and memory formation.
To confirm these findings, the researchers observed living brain cells to find out how brain messaging responds to the BDNF. The ones that are never translated into the production of proteins can build up within cells. The researchers observed through microscope a lab dish that contained brain cells that had been denoted with a fluorescent molecule. This labeled the formations with glowing spots. Those cells treated with BDNF cells increased in size and number, indicated by the glowing spots. The researchers learned that BDNF uses the microRNA to deliver messages to the spots, where they can be dispelled from the translating apparatus that renders them into proteins.
Meffert said, “Monitoring these fluorescent complexes gave us a window that we needed to understand how BDNF is able to target the production of only certain proteins that help neurons to grow and make learning possible.” He goes on to say that because the team is now aware of how BDNF increases proteins involved in learning and memory formation, they will be able to explore a possible therapy targeted to improve the mechanism in order to treat patients with mental disorders and neurodegenerative diseases.
“Making Memories: How 1 Protein Does It”. (March 5, 2012). Neuroscience News. March 9, 2012. http://neurosciencenews.com/bdnf-micro-rna-protein-making-memories/.
March 31, 2012 § Leave a comment
A study published in the online Journal of Alzheimer’s Disease reports a critical discovery that will effect the development of new Alzheimer’s drugs as well as earlier detection for prevention. The FKBP52 protein may prevent the hyperphosphorylation of the Tau protein, keeping it from turning pathogenic.
The FKBP52 protein was discovered by Professor Etienne Baulieu twenty years ago. The hyperphosphorylation of the Tau protein is responsible for a number of cerebral neurodegenerative diseases, including Alzheimer’s Disease (AD). The current work is being carried out by Professor Baulieu and his research team at Inserm (National Institute for Medical Research in France).
It is believed that many neurodegenerative diseases are characterized by the accumulation of pathological hyperphosphorylated forms of Tau protein into structures called “Tau tangles.” Beyond this, there is limited knowledge about the Tau protein’s role in the development of AD. The means of Tau toxicity is uncertain so there are no drugs targeting the protein, nor any biomarkers that predict the risk of a future “Tauopathy”. Professor Baulieu and his team decided to concentrate on the Tau abnormalities. They were the first to discover, in 2012, an interaction between Tau and the FKBP52 protein.
The current research advances Baulieu’s previous research. It demonstrates a strong relationship between high levels of hyperphosphorylated Tau protein and reduced levels of FKBP52 in brain cells, from patients who have died as a result of Alzheimer’s Disease, compared with normal brain cells. This implies the anomalous production of pathogenic Tau is controlled by FKBP52 because when FKBP52 is reduced in the nerve cells of AD patients, pathogenic Tau accumulates and causes the degeneration of brain cells.
A basis for a predictive test for AD could be the early measurement of FKBP52 levels (before the onset of clinical symptoms). Also, new compounds that modulate FKBP52’s activity could develop into a new cohort of treatments for the disease.
Professor Baulieu said, “There is still a worrying lack of research into the causes of age-related brain disorders such as Alzheimer’s disease and dementia. I founded the Institut Baulieu with the aim of being able to treat and even prevent these diseases. Research on Tau has been very limited, and until recently, I was among the few scientists focusing on Tau pathology. The discovery of the FKBP52 protein is the only ‘anti-Tau’ perspective so far. Its reduced production in the brains of Alzheimer’s patients marks a turning point in understanding this complex disease. I believe it takes us one step closer to developing an effective treatment and possible predictive tests for the increasing number of people who may develop Alzheimer’s Disease in our ageing societies.”
“New Hope for Treating Alzheimer’s Disease: A Role for the FKBP52 Protein”. (March 20, 2012). Neuroscience News. March 24, 2012. http://neurosciencenews.com/fkbp52-protein-alzheimers-disease-anti-tau/.