Posts tagged neurons
Articles and news from the latest research reports.
The brain’s got rhythm: Extracting temporal patterns from visual input
To understand how the brain recognizes speech, appreciates music and performs other higher-level functions, it is necessary to understand how neural systems process temporal information. Recently, scientists at Beijing Normal University studied a simple but powerful network model by which a neural system can extract long-period (several seconds in duration) external rhythms from visual input. Moreover, the study’s findings suggest that a large neural network with a scale-free topology – that is, a network in which the probability distribution of the number of connections between its nodes follows a power law – is analogous to a repertoire where neural loops and chains form the mechanism by which exogenous rhythms are learned. Importantly, their model suggests that the brain does not necessarily require an internal clock to acquire and memorize these rhythms.
Prof. Si Wu and Prof. Gang Hu discussed the paper that they and their co-authors recently published in Proceedings of the National Academy of Sciences. “The challenge for generating slow oscillation – that is, on the order of seconds – in a neural system is that the dynamics of single neurons and neuronal synapses are too short,” Wu tells Medical Xpress. “In other words, for an unstructured network, a strong input will typically generate a strong transient response, and hence the system is unable to retain slow oscillation.” To solve this problem, the scientists came up with the idea of using the propagation of activity along a long loop of neurons to hold the rhythm information. “Neurons in the loop need to have low-connectivity degrees to avoid inducing synchronous firing of the network,” Hu adds.
Hu also comments on constructing a network model with scale-free structure. “We knew that a scale-free network had the structure we wanted – namely, it consists of a large number of low-degree neurons which can form different sizes of loops and chains, as well as a few hub neurons which can trigger synchronous firing of the network. Furthermore,” he continues, “we didn’t want hub neurons to be easily elicited; otherwise, the network will always get into epileptic firings.” To solve this problem, the researchers required that the neuronal interactions have the proper form to easily activate low-degree neuron while also making it hard to activate hub neurons. Wu point out that biologically plausible electrical synapses and scaled chemical synapses naturally hold this property.
Wu says that the researchers did not develop innovative techniques in this study. “Our main contribution was to propose a simple and yet effective mechanism for a neural system encoding temporal information,” he explains, noting that this mechanism consists of five key points:
1. Hub neurons, through their massive connections to others, induce synchronous firing of the network
2. Loops of low-degree neurons hold rhythm information, with the loop size deciding the rhythm
3. Proper electrical or scaled chemical neuronal synapses ensure that activating a hub neuron is difficult in comparison with a low-degree neuron – and also avoids epileptic network firing, in which periods of rapid spiking are followed by quiescent, silent, periods
4. A large-size scale-free network is like a reservoir, which contains a large number and various sizes of loops and chains formed by low-degree neurons, and hence can encode a broad range of rhythmic information
5. When an external rhythmic input is presented, the network selects a loop from its reservoir, with the loop size matching the input rhythm – and this matching operation can be achieved by a synaptic plasticity rule
The team’s findings imply that in terms of neural information processing, a neural system can use loops and chains of connected neurons to hold the memory trace of input information and, that the latter might serve as the substrate to process temporal events. “These implications for temporal information processing in neural systems have two aspects,” Wu points out. “Firstly, there’s been a long-standing debate on whether the brain has a global clock that counts time and coordinates temporal events. Our study suggests that this is not necessary: By using intrinsic network dynamics, the neural system can process temporal information in a distributed manner.”
Secondly, Wu continues, the brain may not use very complicated strategies to process temporal information, but by fully utilizing its enormous number of neurons, rather simple ones. “Our study suggests that a large size scale-free network has various lengths of loops and chains to hold different rhythms of inputs, making information encoding very simple. This is not economically efficient, but it simplifies computation, which could be crucial for animals responding quickly in a naturally competitive environment.”
In the presence of an external rhythmic input, Wu says that the neural system responds and holds the residual activity as the memory trace of the input for a sufficiently long time. If this input is repetitively presented, neuron pairs which fire together become connected through the biological synaptic plasticity rule, and thereby a loop matching the input rhythm is established.
Hu tells Medical Xpress that the network topology is not required to be perfectly scale-free, but rather that the network consists of a few neurons having many connections and a large number of neurons with few connections. “For the convenience of analysis, we considered a scale-free network in which the distribution of neuronal connections satisfying a power law. However, in practice, we don’t need such a strong condition. Rather, what we really need is a large number of low-degree neurons forming loops and chains, and a few hub neurons triggering synchronous firing. In other words, scale-free topology is the sufficient, but not the necessary, condition for our model to work.” Although the researchers focused on the visual system and have not applied their model to the auditory system, Hi suspects that it can be applied to the latter, where temporal processing is more critical.
Moving forward, the scientists’ next step is to build large networks having a similar structure but with more realistic neurons and synapses. “Based on this model,” Wu concludes, “we can explore how temporal information encoded in the way proposed in our model is involved in higher brain functions.” Moreover, other dynamical systems which generate slow oscillation and need to hold temporal information by network dynamics might benefit from our study.”
Study breaks blood-brain barriers to understanding Alzheimer’s
A study in mice shows a breakdown of the brain’s blood vessels may amplify or cause problems associated with Alzheimer’s disease. The results published in Nature Communications suggest that blood vessel cells called pericytes may provide novel targets for treatments and diagnoses.
“This study helps show how the brain’s vascular system may contribute to the development of Alzheimer’s disease,” said study leader Berislav V. Zlokovic, M.D. Ph.D., director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of the University of Southern California, Los Angeles. The study was co-funded by the National Institute of Neurological Diseases and Stroke (NINDS) and the National Institute on Aging (NIA), parts of the National Institutes of Health
Alzheimer’s disease is the leading cause of dementia. It is an age-related disease that gradually erodes a person’s memory, thinking, and ability to perform everyday tasks. Brains from Alzheimer’s patients typically have abnormally high levels of plaques made up of accumulations of beta-amyloid protein next to brain cells, tau protein that clumps together to form neurofibrillary tangles inside neurons, and extensive neuron loss.
Vascular dementias, the second leading cause of dementia, are a diverse group of brain disorders caused by a range of blood vessel problems. Brains from Alzheimer’s patients often show evidence of vascular disease, including ischemic stroke, small hemorrhages, and diffuse white matter disease, plus a buildup of beta-amyloid protein in vessel walls. Furthermore, previous studies suggest that APOE4, a genetic risk factor for Alzheimer’s disease, is linked to brain blood vessel health and integrity.
“This study may provide a better understanding of the overlap between Alzheimer’s disease and vascular dementia,” said Roderick Corriveau, Ph.D., a program director at NINDS.
One hypothesis about Alzheimer’s disease states that increases in beta-amyloid lead to nerve cell damage. This is supported by genetic studies that link familial forms of the disease to mutations in amyloid precursor protein (APP), the larger protein from which plaque-forming beta-amyloid molecules are derived. Nonetheless, previous studies on mice showed that increased beta-amyloid levels reproduce some of the problems associated with Alzheimer’s. The animals have memory problems, beta-amyloid plaques in the brain and vascular damage but none of the neurofibrillary tangles and neuron loss that are hallmarks of the disease.
In this study, the researchers show that pericytes may be a key to whether increased beta-amyloid leads to tangles and neuron loss.
Pericytes are cells that surround the outside of blood vessels. Many are found in a brain plumbing system, called the blood-brain barrier. It is a network that exquisitely controls the movement of cells and molecules between the blood and the interstitial fluid that surrounds the brain’s nerve cells. Pericytes work with other blood-brain barrier cells to transport nutrients and waste molecules between the blood and the interstitial brain fluid.
To study how pericytes influence Alzheimer’s disease, Dr. Zlokovic and his colleagues crossbred mice genetically engineered to have a form of APP linked to familial Alzheimer’s with ones that have reduced levels of platelet-derived growth factor beta receptor (PDGFR-beta), a protein known to control pericyte growth and survival. Previous studies showed that PDGFR-beta mutant mice have fewer pericytes than normal, decreased brain blood flow, and damage to the blood-brain barrier.
“Pericytes act like the gatekeepers of the blood-brain barrier,” said Dr. Zlokovic.
Both the APP and PDGFR-beta mutant mice had problems with learning and memory. Crossbreeding the mice slightly enhanced these problems. The mice also had increased beta-amyloid plaque deposition near brain cells and along brain blood vessels. Surprisingly, the brains of the crossbred mice had enhanced neuronal cell death and extensive neurofibrillary tangles in the hippocampus and cerebral cortex, regions that are typically affected during Alzheimer’s.
“Our results suggest that damage to the vascular system may be a critical step in the development of full-blown Alzheimer’s disease pathology,” said Dr. Zlokovic.
Further experiments suggested that pericytes may transport beta-amyloid across the blood-brain barrier into the blood and showed that crossbreeding the mice slowed the rate at which beta-amyloid was cleared away from nerve cells in the brain.
Next, the researchers addressed how beta-amyloid may affect the vascular system. The crossbred mutants had more pericyte death and more damage to the blood-brain barrier than the PDGFR-beta mutant mice, suggesting beta-amyloid may enhance vascular damage. The investigators also confirmed previous findings showing that beta-amyloid accumulation leads to pericyte death.
Dr. Zlokovic and his colleagues concluded that their results support a two-hit vascular hypothesis of Alzheimer’s. The hypothesis states that the toxic effects of increased beta-amyloid deposition on pericytes in aged blood vessels leads to a breakdown of the blood-brain barrier and a reduced ability to clear amyloid from the brain. In turn, the progressive accumulation of beta-amyloid in the brain and death of pericytes may become a damaging feedback loop that causes dementia. If true, then pericytes and other blood-brain barrier cells may be new therapeutic targets for treating Alzheimer’s disease.
(Source: ninds.nih.gov)
Dietary Amino Acids Relieve Sleep Problems after Traumatic Brain Injury in Animals
Scientists who fed a cocktail of key amino acids to mice improved sleep disturbances caused by brain injuries in the animals. These new findings suggest a potential dietary treatment for millions of people affected by traumatic brain injury (TBI)—a condition that is currently untreatable.
“If this type of dietary treatment is proved to help patients recover function after traumatic brain injury, it could become an important public health benefit,” said study co-leader Akiva S. Cohen, Ph.D., a neuroscientist at The Children’s Hospital of Philadelphia (CHOP).
Cohen is the co-senior author of the animal TBI study appearing today in Science Translational Medicine. He collaborated with two experts in sleep medicine: co-senior author Allan I. Pack, M.D., Ph.D., director of the Center for Sleep and Circadian Neurobiology in the Perelman School of Medicine at the University of Pennsylvania; and first author Miranda M. Lim, M.D., Ph.D., formerly at the Penn Sleep Center, and now on faculty at the Portland VA Medical Center and Oregon Health and Science University.
Every year in the U.S., an estimated 2 million people suffer a TBI, accounting for a major cause of disability across all age groups. Although 75 percent of reported TBI cases are milder forms such as concussion, even concussion may cause chronic neurological impairments, including cognitive, motor and sleep problems.
“Sleep disturbances, such as excessive daytime sleepiness and nighttime insomnia, disrupt quality of life and can delay cognitive recovery in patients with TBI,” said Lim, a neurologist and sleep medicine specialist. Although physicians can relieve the dangerous swelling that occurs after a severe TBI, there are no existing treatments to address the underlying brain damage associated with neurobehavioral problems such as impaired memory, learning and sleep patterns.
Cohen and team investigate the use of selected branched chain amino acids (BCAA)—precursors of the neurotransmitters glutamate and GABA, which are involved in communication among neurons and help to maintain a normal balance in brain activity. His research team previously showed that a BCAA diet restored cognitive ability in brain-injured mice. The current study was the first to analyze sleep-wake patterns in an animal model.
Comparing mice with experimentally induced mild TBI to uninjured mice, the scientists found the injured mice were unable to stay awake for long periods of time. The injured mice had lower activity among orexin neurons, which help to maintain the animals’ wakefulness. This is similar to results in human studies showing decreased orexin levels in the spinal fluid after TBI.
In the current study, the dietary therapy restored the orexin neurons to a normal activity level and improved wakefulness in the brain-injured mice. EEG recordings also showed improved brain wave patterns among the mice that consumed the BCAA diet.
“These results in an animal model provide a proof-of-principle for investigating this dietary intervention as a treatment for TBI patients,” said Cohen. “If a dietary supplement can improve sleeping and waking patterns as well as cognitive problems, it could help brain-injured patients regain crucial functions.” Cohen cautioned that current evidence does not support TBI patients medicating themselves with commercially available amino acids.
(Source: chop.edu)
Staying ahead of Huntington’s disease
Huntington’s disease is a devastating, incurable disorder that results from the death of certain neurons in the brain. Its symptoms show as progressive changes in behavior and movements.
The neurodegenerative disease is caused by a defect in the huntingtin gene (Htt) that causes an abnormal expansion in a part of DNA, called a CAG codon or triplet that codes for the amino acid glutamine. A healthy version of the Htt gene has between 20 and 23 CAG triplets. The mutational expansion in Htt can lead to long repeats of the CAG triplet, resulting in the mutant protein having a long sequence of several glutamine residues called a polyglutamine tract. This CAG triplet expansion in unrelated genes is the root of at least nine neurodegenerative disorders, including Huntington’s disease.
Rohit Pappu, PhD, professor of biomedical engineering at Washington University in St. Louis, and his colleagues in the School of Engineering & Applied Science and in the School of Medicine, are working to understand how expanded polyglutamine tracts form the types of supramolecular structures that are presumed to be toxic to neurons – a feature that polyglutamine expansions share with proteins associated with Alzheimer’s disease and Parkinson’s disease.
In recent work, Pappu and his research team showed that the amino acid sequences on either side of the polyglutamine tract within Htt can act as natural gatekeepers because they control the fundamental ability of polyglutamine tracts to form structures that are implicated in cellular toxicity. The results were published in PNAS Early Edition Nov.25.
“These are progressive onset disorders,” Pappu says. “The longer the polyglutamine tract gets, the more severe the disease, and the symptoms worsen with age. Our results are exciting because it means that any success we have in mimicking the effects of naturally occurring gatekeepers would be a significant step forward. And mechanistic studies are important in this regard because they enable us to learn from nature’s own strategies.
“Previous studies from other labs showed that the toxic effects of polyglutamine expansions are tempered by the sequence contexts of polyglutamine tracts in Htt, not just the lengths of the polyglutamine tracts”, Pappu says.
He and his research team focused on understanding the effects of sequence stretches that lie on either side of the polyglutamine tract in Htt. The results show that the N-terminal stretch accelerates the formation of ordered structures that are presumed to be benign to cells, whereas the C-terminal stretch slows the overall transition into structures that are expected to create trouble for cells, suggesting that these naturally occurring sequences behave as gatekeepers.
“It appears that where polyglutamine stretches are of functional importance, nature has ensured that they are flanked by gatekeeping sequences,” Pappu says.
Pappu and his team are now working to find way s to mimic the effects of the N- and C-terminal flanking sequences from Htt. His team is working closely with Marc Diamond, MD, the David Clayson Professor of Neurology at the School of Medicine, to understand how naturally occurring proteins interact with flanking sequences and see if they can coopt them to ameliorate the toxic functions in the polyglutamine expansions.
(Source: engineering.wustl.edu)
To learn new motor skills, the brain must be plastic: able to rapidly change the strengths of connections between neurons, forming new patterns that accomplish a particular task. However, if the brain were too plastic, previously learned skills would be lost too easily.
A new computational model developed by MIT neuroscientists explains how the brain maintains the balance between plasticity and stability, and how it can learn very similar tasks without interference between them.
The key, the researchers say, is that neurons are constantly changing their connections with other neurons. However, not all of the changes are functionally relevant — they simply allow the brain to explore many possible ways to execute a certain skill, such as a new tennis stroke.
“Your brain is always trying to find the configurations that balance everything so you can do two tasks, or three tasks, or however many you’re learning,” says Robert Ajemian, a research scientist in MIT’s McGovern Institute for Brain Research and lead author of a paper describing the findings in the Proceeding of the National Academy of Sciences the week of Dec. 9. “There are many ways to solve a task, and you’re exploring all the different ways.”
As the brain explores different solutions, neurons can become specialized for specific tasks, according to this theory.
Noisy circuits
As the brain learns a new motor skill, neurons form circuits that can produce the desired output — a command that will activate the body’s muscles to perform a task such as swinging a tennis racket. Perfection is usually not achieved on the first try, so feedback from each effort helps the brain to find better solutions.
This works well for learning one skill, but complications arise when the brain is trying to learn many different skills at once. Because the same distributed network controls related motor tasks, new modifications to existing patterns can interfere with previously learned skills.
“This is particularly tricky when you’re learning very similar things,” such as two different tennis strokes, says Institute Professor Emilio Bizzi, the paper’s senior author and a member of the McGovern Institute.
In a serial network such as a computer chip, this would be no problem — instructions for each task would be stored in a different location on the chip. However, the brain is not organized like a computer chip. Instead, it is massively parallel and highly connected — each neuron connects to, on average, about 10,000 other neurons.
That connectivity offers an advantage, however, because it allows the brain to test out so many possible solutions to achieve combinations of tasks. The constant changes in these connections, which the researchers call hyperplasticity, is balanced by another inherent trait of neurons — they have a very low signal to noise ratio, meaning that they receive about as much useless information as useful input from their neighbors.
Most models of neural activity don’t include noise, but the MIT team says noise is a critical element of the brain’s learning ability. “Most people don’t want to deal with noise because it’s a nuisance,” Ajemian says. “We set out to try to determine if noise can be used in a beneficial way, and we found that it allows the brain to explore many solutions, but it can only be utilized if the network is hyperplastic.”
This model helps to explain how the brain can learn new things without unlearning previously acquired skills, says Ferdinando Mussa-Ivaldi, a professor of physiology at Northwestern University.
“What the paper shows is that, counterintuitively, if you have neural networks and they have a high level of random noise, that actually helps instead of hindering the stability problem,” says Mussa-Ivaldi, who was not part of the research team.
Without noise, the brain’s hyperplasticity would overwrite existing memories too easily. Conversely, low plasticity would not allow any new skills to be learned, because the tiny changes in connectivity would be drowned out by all of the inherent noise.
The model is supported by anatomical evidence showing that neurons exhibit a great deal of plasticity even when learning is not taking place, as measured by the growth and formation of connections of dendrites — the tiny extensions that neurons use to communicate with each other.
Like riding a bike
The constantly changing connections explain why skills can be forgotten unless they are practiced often, especially if they overlap with other routinely performed tasks.
“That’s why an expert tennis player has to warm up for an hour before a match,” Ajemian says. The warm-up is not for their muscles, instead, the players need to recalibrate the neural networks that control different tennis strokes that are stored in the brain’s motor cortex.
However, skills such as riding a bicycle, which is not very similar to other common skills, are retained more easily. “Once you’ve learned something, if it doesn’t overlap or intersect with other skills, you will forget it but so slowly that it’s essentially permanent,” Ajemian says.
The researchers are now investigating whether this type of model could also explain how the brain forms memories of events, as well as motor skills.
The Smoking Gun: Fish Brains and Nicotine
In researching neural pathways, it helps to establish an analogous relationship between a region of the human brain and the brains of more-easily studied animal species. New work from a team led by Carnegie’s Marnie Halpern hones in on one particular region of the zebrafish brain that could help us understand the circuitry underlying nicotine addiction. It is published the week of December 9 by Proceedings of the National Academy of Sciences.
The mammalian habenular nuclei, in a little-understood and difficult-to-access part of the brain, are involved in regulating both dopamine and serotonin, two neurotransmitters involved in motor control, mood, learning, and addiction. But unlike the mammalian habenulae, the habenular nuclei of fish are located dorsally, making them easy for scientists to access and study. However, some outstanding questions remained about the properties of the zebrafish habenulae, creating a roadblock for truly linking these structures as analogous in fish and humans. In particular, it was unresolved whether zebrafish habenular neurons produce the neurotransmitter acetylcholine, which is enriched in this region of the mammalian brain and activates the same receptors to which nicotine is known to bind.
The new work by lead author Elim Hong and colleagues confirms that the pathway between the habenula and another part of the brain called the midbrain interpenduncular nucleus utilizes acetylcholine in zebrafish, as it does in humans. The work also shows that there is a left-right difference in this part of the fish brain.
The purpose of this asymmetry is unknown, but, as demonstrated by electrophysiological recordings with collaborator Jean-Marie Mangin of the University of Pierre and Marie Curie, it results in differences in neural activity between the brain hemispheres. Other research in Halpern’s lab indicates that such left-right differences could influence behavior. Hong performed these experiments through a European Molecular Biology Organization Short-Term Fellowship while hosted in the laboratory of Claire Wyart in Paris, France.
The team further showed that this acetylcholine pathway in zebrafish responds in a similar way to nicotine as does the analagous pathway in the mammalian brain. This makes the zebrafish a good model for studying the brain chemistry of nicotine addiction.
“Our work demonstrates broader uses for zebrafish in studying the function of the habenula and addresses a major weakness in the field, which was the poor characterization of neurotransmitter identity in this area,” said Hong. “Going forward, these results will help us study how brain circuitry influences nicotine addiction.”
Heads or tails? Random fluctuations in brain cell activity may determine toss-up decisions
Life presents us with choices all the time: salad or pizza for lunch? Tea or coffee afterward? How we make these everyday decisions has been a topic of great interest to economists, who have devised theories about how we assign values to our options and use those values to make decisions.
An emerging field of study known as neuroeconomics is combining the economists’ insights with scientific study of the brain to learn more about decision-making processes and how they can go awry. In the Dec. 8 issue of Neuron, one of the field’s founders reports new links between brain cell activity and choices where two options have equal appeal.
“Neuroeconomics is not only helpful for the development of better economic theory, it is also relevant from a clinical point of view,” said author Camillo Padoa-Schioppa, PhD, assistant professor of neurobiology, economics and of biomedical engineering at Washington University School of Medicine in St. Louis. “There are a number of conditions that involve impaired economic decision-making, including drug addiction, brain injury, some forms of dementia, schizophrenia and obsessive-compulsive disorder.”
Scientists know that the orbitofrontal cortex, a region of the brain behind and above the eyes, plays a key role in making decisions. Patients with injuries to this part of the brain are often spectacularly bad at making decisions. They may do things like abandon longstanding relationships, gamble away money or lose it to swindlers, or become addicted to drugs.
To study the roles brain cells play in decision-making, Padoa-Schioppa developed a system for presenting primates a choice between two drinks, such as grape juice or apple juice. The type and amount of the drink varies, and researchers record the activity of individual brain neurons as the primates choose.
Based on the decisions of a single animal over multiple trials, scientists infer the subjective value the animal assigns to each drink and then look for ways this value is encoded in brain cells.
“For example, if we offer a larger amount of apple juice versus a smaller amount of grape juice, and the primate chooses each option equally often, we infer that this primate likes the grape juice better than the apple juice,” he explained. “The primate could be getting more juice by choosing the cup with apple juice, but it doesn’t always do so. That implies that the primate values grape juice more than apple juice.”
In 2006, Padoa-Schioppa and Harvard colleague John Assad, PhD, won international attention for using this system to identify brain cells whose firing rates encoded the subjective value of drink choices.
In a new analysis of data from the original experiment, Padoa-Schioppa showed that different groups of cells in the orbitofrontal cortex reflect different stages of the decision-making process.
“Some neurons encode the value of individual drinks; other neurons encode the choice outcome in a binary way ‒ these cells are either firing or silent depending on the chosen drink,” he explained. “Yet other neurons encode the value of the chosen option.”
Padoa-Schioppa then examined how different groups of cells determine decisions between options of equal value. He showed that toss-up decisions seemed to depend on changes in the initial state of the network of neurons in the orbitofrontal cortex.
“The fluctuations in the network took place before the primates were even offered a choice of juices, but they seem to somehow bias the decision,” Padoa-Schioppa said. “Neuronal signals are always noisy. In essence, close-call decisions are partly determined by random noise.”
He also found that decisions on choices of equal value were linked to the ease or difficulty with which nerve cells in parts of the orbitofrontal cortex communicate with each other. This property, known as synaptic efficacy, can be adjusted by the brain as part of the process of encoding information.
According to Padoa-Schioppa, these results provide new insights into the neuronal circuits that underlie economic decisions. He and his colleagues are using them to create a computational model of decision-making.
“The next step is to test that model,” Padoa-Schioppa said. “For example, we would like to bias decisions by artificially manipulating the activity of specific groups of cells.”
(Source: news.wustl.edu)
Human Stem Cells Predict Efficacy of Alzheimer Drugs
Researchers from the University of Bonn use reprogrammed patient neurons for drug testing
Why do certain Alzheimer medications work in animal models but not in clinical trials in humans? A research team from the University of Bonn and the biomedical enterprise LIFE & BRAIN GmbH has been able to show that results of established test methods with animal models and cell lines used up until now can hardly be translated to the processes in the human brain. Drug testing should therefore be conducted with human nerve cells, conclude the scientists. The results are published by Cell Press in the journal “Stem Cell Reports”.
In the brains of Alzheimer patients, deposits form that consist essentially of beta-amyloid and are harmful to nerve cells. Scientists are therefore searching for pharmaceutical compounds that prevent the formation of these dangerous aggregates. In animal models, certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to a reduced formation of harmful beta-amyloid variants. Yet, in subsequent clinical studies, these NSAIDs failed to elicit any beneficial effects.
"The reasons for these negative results have remained unclear for a long time", says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology of the University of Bonn and CEO of LIFE & BRAIN GmbH. "Remarkably, these compounds were never tested directly on the actual target cells – the human neuron", adds lead author Dr. Jerome Mertens of Prof. Brüstle’s team, who now works at the Laboratory of Genetics in La Jolla (USA). This is because, so far, living human neurons have been extremely difficult to obtain. However, with the recent advances in stem cell research it has become possible to derive limitless numbers of brain cells from a small skin biopsy or other adult cell types.
Scientists transform skin cells into nerve cells
Now a research team from the Institute for Reconstructive Neurobiology and the Department of Neurology of the Bonn University Medical Center together with colleagues from the LIFE & BRAIN GmbH and the University of Leuven (Belgium) has obtained such nerve cells from humans. The researchers used skin cells from two patients with a familial form of Alzheimer’s Disease to produce so-called induced pluripotent stem cells (iPS cells), by reprogramming the body’s cells into a quasi-embryonic stage. They then transformed the resulting so-called “jack-of-all-trades cells” into nerve cells.
Using these human neurons, the scientists tested several compounds in the group of non-steroidal anti-inflammatory drugs. As control, the researchers used nerve cells they had obtained from iPS cells of donors who did not have the disease. Both in the nerve cells obtained from the Alzheimer patients and in the control cells, the NSAIDs that had previously tested positive in the animal models and cell lines typically used for drug screening had practically no effect: The values for the harmful beta-amyloid variants that form the feared aggregates in the brain remained unaffected when the cells were treated with clinically relevant dosages of these compounds.
Metabolic processes in animal models differ from humans
"In order to predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells", concludes Prof. Brüstle’s colleague Dr. Philipp Koch, who led the study. Why do NSAIDs decrease the risk of aggregate formation in animal experiments and cell lines but not in human neurons? The scientists explain this with differences in metabolic processes between these different cell types. "The results are simply not transferable", says Dr. Koch.
The scientists now hope that in the future, testing of potential drugs for the treatment of Alzheimer’s disease will be increasingly conducted using neurons obtained from iPS cells of patients. “The development of a single drug takes an average of ten years”, says Prof. Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer medications could be greatly streamlined”.
(Source: www3.uni-bonn.de)
Study Treats Alzheimer’s by Delivering Protein Across Blood-Brain Barrier
The body is structured to ensure that any invading organisms have a tough time reaching the brain, an organ obviously critical to survival. Known as the blood-brain barrier, cells that line the brain and spinal cord are tightly packed, making it difficult for anything besides very small molecules to cross from the bloodstream into the central nervous system. While beneficial, this blockade also stands in the way of delivering drugs intended to treat neurological disorders, such as Alzheimer’s.
In a new study published in the journal Molecular Therapy, University of Pennsylvania researchers have found a way of traversing the blood-brain barrier, as well as a similar physiological obstacle in the eye, the retinal-blood barrier. By pairing a receptor that targets neurons with a molecule that degrades the main component of Alzheimer’s plaques, the biologists were able to substantially dissolve these plaques in mice brains and human brain tissue, offering a potential mechanism for treating the debilitating disease, as well as other conditions that involve either the brain or the eyes.
The work was led by Henry Daniell, a professor in Penn’s School of Dental Medicine’s departments of biochemistry and pathology and director of translational research. The research team included Penn Dental Medicine’s Neha Kohli, Donevan R. Westerveld, Alexandra C. Ayache and Sich L. Chan. Co-authors at the University of Florida College of Medicine, including Amrisha Verma, Pollob Shil, Tuhina Prasad, Ping Zhu and Quihong Li, analyzed retinal tissues.
The researchers began their work by considering how they might breach the blood-brain barrier. Daniell hypothesized that a molecule might be permitted to cross if it was attached to a carrier that is able to pass over, as a sort of molecular crossing guard. The protein cholera toxin B, or CTB, a non-toxic carrier currently approved for use in humans by the Food and Drug Administration, is used in this study to traverse the blood-brain barrier.
They next identified a protein that could clear the plaques that are found in the brains of Alzheimer’s patients. These plaques, which are believed to cause the dementia associated with the disease, are made up of tangles of amyloid beta (Aβ), a protein that is found in soluble form in healthy individuals. Noting that myelin basic protein (MBP) has been shown to degrade Aβ chains, the team decided to couple it with CTB to see if MBP would be permitted to cross.
“These tangles of beta amyloid are known to be the problem in Alzheimer’s,” says Daniell. “So our idea was to chop the protein back to their normal size so they wouldn’t form these tangles.”
To test this idea, the Penn-led team first exposed healthy mice to the CTB-MBP compound by feeding them capsules of freeze-dried leaves that had been genetically engineered to express the fused proteins, a method developed and perfected by Daniell over many years as a means of orally administering various drugs and vaccines. Adding a green-fluorescent protein to the CTB carrier, the researchers tracked the “glow” to see where the mice took up the protein. They found the glowing protein in both the brain and retina.
“When we found the glowing protein in the brain and the retina we were quite thrilled,” said Daniell. “If the protein could cross the barrier in healthy mice, we thought it was likely that it could cross in Alzheimer’s patients brains, because their barrier is somewhat impaired.”
When CTB was not part of the fused protein, they did not see this expression, suggesting that their carrier protein, the crossing guard, was an essential part of delivering their protein of interest.
To then see what MBP would do once it got to the brain, Daniell and colleagues exposed the CTB-MBP protein to the brains of mice bred to have an Alzheimer’s disease. They used a stain that binds to the brain plaques and found that exposure to the CTB-MBP compound resulted in reductions of staining up to 60 percent, indicating that the plaques were dissolving.
Gaining confidence that their compound was appropriately targeting the plaques, the researchers worked with the National Institutes of Health to obtain brain tissue from people who died of Alzheimer’s and performed the same type of staining. Their results showed a 47 percent decrease in staining in the inferior parietal cortex, a portion of the brain found to play an important role in the development of Alzheimer’s-associated dementia.
As a final step, the researchers fed the CTB-MBP-containing capsules to 15-month-old mice, the equivalent of 80 or more human years, bred to develop Alzheimer’s disease. After three months of feeding, the mice had reductions in Aβ plaques of up to 70 percent in the hippocampus and up to 40 percent in the cortex, whereas mice fed capsules that contained lettuce leaves without CTB-MBP added and mice that were not fed any capsules did not have any reduction in evidence of brain plaques.
Because Alzheimer’s patients have also been found to have plaques in their eyes, the researchers examined the eyes of the mice fed the protein. They found that, indeed, the Alzheimer’s-mice did have retinal plaques, but those fed the CBP-MBP compound had undetectable Aβ plaques in their retinae.
“Really no one knows whether the memory problems that people who have Alzheimer’s disease are due to the dementia or problems with their eyes,” Daniell said. “Here we show it may be both, and that we can dissolve the plaques through an oral route.”
Daniell hopes that this technique of delivering proteins across the blood-brain and blood-retina barriers could serve to treat a variety of diseases beyond Alzheimer’s. Several current clinical trials have failed because of an inability to deliver drugs to the brain. Currently, treatments of some eye conditions must physically penetrate the retina with an injection, an approach that requires anesthesia and risks retinal detachment. Treatment with an ingestible capsule would be safer, easier, and more cost-effective.
As a next step, Daniell hopes to collaborate with Alzheimer’s experts at Penn to advance these studies and add a behavioral component to determine whether the CBP-MBP compound not only removes plaques but also improves the memory and functioning of mice with the Alzheimer’s disease.
Alzheimer’s drug discovery: Looking under the right ROCK
A discovery by Emory Alzheimer’s Disease Research Center and Scripps Research Institute scientists could lead to drugs that slow Alzheimer’s disease progression.
A straightforward drug strategy against Alzheimer’s is to turn down the brain’s production of beta-amyloid, the key component of the disease’s characteristic plaques. A toxic fragment of a protein found in healthy brains, beta-amyloid accumulates in the brains of people affected by the disease.
The enzyme that determines how much beta-amyloid brain cells generate is called BACE (beta-secretase or beta-site APP cleaving enzyme). Yet finding drugs that inhibit that elusive enzyme has been far from straightforward.
Now researchers have identified a way to shut down production of beta-amyloid by diverting BACE to a different part of the cell and inhibiting its activity. The results were published this week in Journal of Neuroscience.
"This is an indirect but highly effective way of blocking BACE, which controls the chokepoint step in beta-amyloid production," says lead author Jeremy Herskowitz, PhD, instructor in neurology at Emory’s Alzheimer’s Disease Research Center.
"Jeremy has found a promising approach toward reducing beta-amyloid production and potentially modifying Alzheimer’s disease progression, something for which there is immense need," says senior author James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Drugs that reduce beta-amyloid production would probably be mostly preventive. However, since amyloid-beta is toxic, such drugs could have some immediate effect on cognitive impairment."
In the paper, Herskowitz and his colleagues demonstrate that a specific inhibitor of the enzyme ROCK2 can cut beta-amyloid production in brain cells by more than 75 percent. Co-author Yangbo Feng, PhD, associate director of medicinal chemistry at Scripps Research Institute in Florida, previously discovered the ROCK2 inhibitor, called SR3677.
Alzheimer’s researchers were already interested in ROCK2 and a related enzyme, ROCK1, because of a connection with NSAIDs (non-steroid anti-inflammatory drugs) such as ibuprofen. Some NSAIDS can inhibit production of a particularly toxic form of beta-amyloid, and scientists believed NSAIDs were exerting their effects through the ROCKs.
Herskowitz first showed that in cultured cells, “knocking down” the ROCK2 gene reduced beta-amyloid production, but knocking down ROCK1 had the opposite effect.
"This says that anytime you’re hitting both ROCKs at once, the effects cancel each other out," he says.
The known drugs that affect the ROCKs seemed to affect both and thus have diminished effects. In contrast, SR3677 inhibits ROCK2 much more effectively than ROCK1, and it offered a way around the obstacle. Herskowitz found that by inhibiting ROCK2, SR3677 diverts BACE to a different part of the cell, where it is less likely to act on beta-amyloid’s parent protein.
He and ADRC colleagues found that ROCK2 levels are higher than usual in tissue samples from brains of patients with Alzheimer’s, including those with mild cognitive impairment, thought to be a precursor stage of the disease.
"There is plenty of ROCK2 in the brain, and its levels are elevated in Alzheimer’s patients, indicating that it’s an excellent drug target," Herskowitz says. "We are eager to pursue more extensive studies of this strategy in animal models of Alzheimer’s."
SR3677 can substantially inhibit beta-amyloid production in an animal model of Alzheimer’s, but so far, this effect has been observed when the drug is injected directly into the brain. More studies are required to learn if SR3677 or related drugs can pass the blood-brain barrier and thus be given by injection or orally, and what side effects could appear. ROCK inhibitors are also being investigated for treating other conditions such as glaucoma, hypertension and multiple sclerosis.
(Source: news.emory.edu)