Posts tagged alzheimer's disease
Articles and news from the latest research reports.
A Brake in the Head: German researchers gain new insights into the working of the brain
Scientists of the Charité – Universitätsmedizin Berlin and the German Center for Neurodegenerative Diseases (DZNE) have managed to acquire new insights into the functioning of a region in the brain that normally is involved in spatial orientation, but is damaged by the Alzheimer’s disease. They investigated how nerve signals are suppressed inside the so-called entorhinal cortex. According to the researchers, this neuronal inhibition leads nerve cells to synchronize their activity. The results of this study are now published in Neuron.
The entorhinal cortex is a link between the brain’s memory centre, the hippocampus, and the other areas of the brain. It is, however, more than an interface that only transfers nervous impulses. The entorhinal cortex also has an independent role in learning and thinking processes. This is particularly applicable for spatial navigation. “We know precious little about how this happens,” says Prof. Dietmar Schmitz, a researcher at the Cluster of Excellence NeuroCure at the Charité – Universitätsmedizin Berlin and Site Speaker for the DZNE in Berlin. “This is why we are investigating in animal models how the nerve cells within the entorhinal cortex are connected with each other.“
Signals wander inside the brain as electrical impulses from nerve cell to nerve cell. In general, signals are not merely forwarded. Rather, operation of the brain critically depends on the fact that the nerve impulses in some situations are activated and in other cases suppressed. A correct balance between suppression and excitation is decisive for all brain processes. “Until now research has mainly concentrated on signal excitation within the entorhinal cortex. This is why we looked into inhibition and detected a gradient inside the entorhinal cortex,” explains Dr. Prateep Beed, lead author of the study. “This means that nerve signals are not suppressed equally. The blockage of the nerve signals is weaker in certain parts of the entorhinal cortex and stronger in others. The inhibition has, so to speak, a spatial profile.”
When the brain is busy, nerve cells often coordinate their operation. In an electroencephalogram (EEG) – a recording of the brain’s electrical activity – the synchronous rhythm of the nerve cells manifests as a periodic pattern. “It is a moot question as to how nerve cells synchronize their behavior and how they bring about such rhythms,” says Beed. As he explains, it is also unclear whether these oscillations are only just a side effect or whether they trigger other phenomena. “But it has been demonstrated that neuronal oscillations accompany learning processes and even happen during sleep. They are a typical feature of the brain’s activity,” describes the scientist. “In our opinion, the inhibitory gradient, which we detected, plays an important role in creating the synchronous rhythm of the nerve cells and the related oscillations.”
In the case of Alzheimer’s, the entorhinal cortex is among the regions of the brain that are the first to be affected. “In recent times, studies related to this brain structure have increased. Here, already in the early stages of Alzheimer’s, one finds the protein deposits that are typical of this disease,” explains Schmitz, who headed the research. “It is also known that patients affected by Alzheimer’s have a striking EEG. Our studies help us to understand how the nerve cells in the entorhinal cortex operate and how electrical activities might get interrupted in this area of the brain.”
Fluorescent compounds allow clinicians to visualize Alzheimer’s disease as it progresses
What if doctors could visualize all of the processes that take place in the brain during the development and progression of Alzheimer’s disease? Such a window would provide a powerful aid for diagnosing the condition, monitoring the effectiveness of treatments, and testing new preventive and therapeutic agents. Now, researchers reporting in the September 18 issue of the Cell Press journal Neuron have developed a new class of imaging agents that enables them to visualize tau protein aggregates, a pathological hallmark of Alzheimer’s disease and related neurodegenerative disorders, directly in the brains of living patients.
In the brains of patients with Alzheimer’s disease, tau proteins aggregate together and become tangled, while fragments of another protein, called amyloid beta, accumulate into deposits or plaques. Tau tangles are not only considered an important marker of neurodegeneration in Alzheimer’s disease but are also a hallmark of non-Alzheimer’s neurodegenerative disorders, tauopathies that do not involve amyloid beta plaques. While imaging technologies have been developed to observe the spread of amyloid beta plaques in patients’ brains, tau tangles were previously not easily monitored in the living patient.
In this latest research in mice and humans, investigators developed fluorescent compounds that bind to tau (called PBBs) and used them in positron emission tomography (PET) tests to correlate the spread of tau tangles in the brain with moderate Alzheimer’s disease progression. “PET images of tau accumulation are highly complementary to images of senile amyloid beta plaques and provide robust information on brain regions developing or at risk for tau-induced neuronal death,” says senior author Dr. Makoto Higuchi, of the National Institute of Radiological Sciences in Japan. “This is of critical significance, as tau lesions are known to be more intimately associated with neuronal loss than senile plaques.”
The advance may also be helpful for diagnosing, monitoring, and treating other neurological conditions because tau tangles are not limited to Alzheimer’s disease but also play a role in various types of dementias and movement disorders.
Study helps deconstruct estrogen’s role in memory
The loss of estrogens at menopause increases a woman’s risk of dementia and Alzheimer’s disease, yet hormone replacement therapy can cause harmful side effects.
Knowing the exact mechanism of estrogen activation in the brain could lead to new targets for drug development that would provide middle-aged women the cognitive benefits of hormone replacement therapy without increasing their risk for cardiovascular disease or breast cancer.
In a new study, Karyn Frick, professor of psychology at the University of Wisconsin-Milwaukee, uncovers details about estrogen’s role in the complex cellular communication system underlying memory formation.
“The receptor mechanisms that regulate estrogen’s ability to enhance memory are still poorly understood,” says Frick. “With this study, we’ve begun to sort out several of the key players needed for estrogens to mediate memory formation.”
The research, published in the The Journal of Neuroscience today, focused on estrogen effects in a brain region called the hippocampus, which deteriorates with age or Alzheimer’s disease. The researchers found that each of the two known estrogen receptors rapidly activate a specific cellular pathway necessary for memory formation in the hippocampus of female mice, but only if they interact with a certain glutamate receptor, called mGluR1.
The study revealed that when this glutamate receptor is blocked, the cell-signaling protein ERK cannot be activated by the potent estrogen, 17β-estradiol. Because ERK activation is necessary for memory formation, estradiol failed to enhance memory among mice in which mGluR1 was blocked.
Frick’s team also found evidence that estrogen receptors and mGluR1 physically interact at the cell membrane, allowing estradiol to influence memory formation within seconds to minutes. Collectively, the data provide the first evidence that the rapid signaling initiated by such interactions is essential for estradiol to enhance memory regulated by the hippocampus.
“Our data suggesting that interactions between estrogen receptors and mGluR1 at the cell membrane are critical for estradiol to enhance memory provides important new information about how estrogens regulate memory formation,” Frick says. “Because membrane proteins are better targets for drug development than proteins inside the cell, these data could lead to a new generation of therapies that provide the cognitive benefits of estrogens without harmful side effects.”
Study finds cognitive enhancers do not improve cognition or function in people with mild cognitive impairment but may cause gastrointestinal issues
Cognitive enhancers—drugs taken to enhance concentration, memory, alertness and moods—do not improve cognition or function in people with mild cognitive impairment in the long term, according to a new study by researchers at St. Michael’s Hospital.
In fact, patients on these medications experienced significantly more nausea, diarrhea, vomiting and headaches, according to the study published today in the Canadian Medical Association Journal.
“Our findings do not support the use of cognitive enhancers for mild cognitive impairment,” wrote Dr. Andrea Tricco and Dr. Sharon Straus, who are both scientists in the hospital’s Li Ka Shing Knowledge Institute. Dr. Straus is also a geriatrician at the hospital.
Mild cognitive impairment is a condition characterized by memory complaints without significant limitations in everyday activity. Between 3 and 42 per cent of people are diagnosed with the condition each year, about 4.6 million people worldwide. Each year about 3 to 17 per cent of people with mild cognitive impairment will develop dementia, such as Alzheimer’s disease. Given the aging population, it’s estimated the number of Canadians with dementia will double to more than 1 million in the next 25 years.
It has been hypothesized that cognitive enhancers may delay the onset of dementia. Families and patients are increasingly requesting these drugs even though their efficacy for patients with mild cognitive impairment has not been established. In Canada, cognitive enhancers can be obtained only with special authorization.
Drs. Tricco and Straus conducted a review of existing evidence to understand the efficacy and safety of cognitive enhancers. They looked at eight randomized trials that compared one of four cognitive enhancers (donepezil, rivastigmine, galantamine or memantine) to a placebo among patients diagnosed with mild cognitive impairment.
While they found short-term benefits to using these drugs on one cognition scale, there were no long-term effects after about a year and a half. No other benefits were observed on the second cognition scale or on function, behaviour, and mortality. As well, patients on these medications experienced significantly more nausea, diarrhea, vomiting and headaches. One study also found a higher risk of a heart condition known as bradycardia (slow heartbeat) among patients who received galantamine.
“Our results do not support the use of cognitive enhancers for patients with mild cognitive impairment,” the authors wrote. “These agents were not associated with any benefit and led to an increase in harms. Patients and their families should consider this information when requesting these medications. Similarly, health care decision-makers may not wish to approve the use of these medications for mild cognitive impairment, because these drugs might not be effective and are likely associated with harm.”
This study was funded by the Drug Safety and Effectiveness Network/Canadian Institutes of Health Research.
Another St. Michael’s study published in the CMAJ in April found no evidence that drugs, herbal products or vitamin supplements help prevent cognitive decline in healthy older adults. That review, led by Dr. Raza Naqvi, a University of Toronto resident, found some evidence that mental exercises, such as computerized memory training programs, might help.
Alzheimer’s patients show striking individual differences in molecular basis of disease
Alzheimer’s disease is thought to be caused by the buildup of abnormal, thread-like protein deposits in the brain, but little is known about the molecular structures of these so-called beta-amyloid fibrils. A study published by Cell Press September 12th in the journal Cell has revealed that distinct molecular structures of beta-amyloid fibrils may predominate in the brains of Alzheimer’s patients with different clinical histories and degrees of brain damage. The findings pave the way for new patient-specific strategies to improve diagnosis and treatment of this common and debilitating disease.
"This work represents the first detailed characterization of the molecular structures of beta-amyloid fibrils that develop in the brains of patients with Alzheimer’s disease," says senior study author Robert Tycko of the National Institutes of Health. "This detailed structural model may be used to guide the development of chemical compounds that bind to these fibrils with high specificity for purposes of diagnostic imaging, as well as compounds that inhibit fibril formation for purposes of prevention or therapy."
Tycko and his team had previously noticed that beta-amyloid fibrils grown in a dish have different molecular structures, depending on the specific growth conditions. Based on this observation, they suspected that fibrils found in the brains of patients with Alzheimer’s disease are also variable and that these structural variations might relate to each patient’s clinical history. But it has not been possible to directly study the structures of fibrils found in patients because of their low abundance in the brain.
To overcome this hurdle, Tycko and his collaborators developed a new experimental protocol. They extracted beta-amyloid fibril fragments from the brain tissue of two patients with different clinical histories and degrees of brain damage and then used these fragments to grow a large quantity of fibrils in a dish. They found that a single fibril structure prevailed in the brain tissue of each patient, but the molecular structures were different between the two patients.
"This may mean that fibrils in a given patient appear first at a single site in the brain, then spread to other locations while retaining the identical molecular structure," Tycko says. "Our study also shows that certain fibril structures may be more likely than others to cause Alzheimer’s disease, highlighting the importance of developing imaging agents that target specific fibril structures to improve the reliability and specificity of diagnosis."
(Source: eurekalert.org)
Alzheimer’s: newly identified protein pathology impairs RNA splicing
Researchers at Emory University School of Medicine’s Alzheimer’s Disease Research Center have identified a previously unrecognized type of pathology in the brains of patients with Alzheimer’s disease.
These tangle-like structures appear at early stages of Alzheimer’s and are not found in other neurodegenerative diseases such as Parkinson’s disease.
What makes these tangles distinct is that they sequester proteins involved in RNA splicing, the process by which instructional messages from genes are cut and pasted together. The researchers show that the appearance of these tangles is linked to widespread changes in RNA splicing in Alzheimer’s brains compared to healthy brains.
The finding could change scientists’ understanding of how the disease develops and progresses, by explaining how genes that have been linked to Alzheimer’s contribute their effects, and could lead to new biomarkers, diagnostic approaches, and therapies.
The results are published in the Proceedings of the National Academy of Sciences, Early Edition.
"We were very surprised to find alterations in proteins that are responsible for RNA splicing in Alzheimer’s, which could have major implications for the disease mechanism," says Allan Levey, MD, PhD, chair of neurology at Emory University School of Medicine and director of the Emory ADRC.
"This is a brand new arena," says James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Many Alzheimer’s investigators have looked at how the disease affects alternative splicing of individual genes. Our results suggest a global distortion of RNA processing is taking place."
This research was led by Drs. Levey, Lah, and Junmin Peng, PhD, who was previously associate professor of genetics at Emory and is now a faculty member at St Jude Children’s Research Hospital. They were aided by collaborators at University of Kentucky, Rush University, and University of Washington as well as colleagues at Emory.
Accumulations of plaques and tangles in the brains of patients with Alzheimer’s disease were first observed more than a century ago. Investigating the proteins in these pathological structures has been central to the study of the disease.
Most experimental treatments for Alzheimer’s have aimed at curbing beta-amyloid, an apparently toxic protein fragment that is the dominant component of amyloid plaques. Other approaches target the abnormal accumulation of the protein tau in neurofibrillary tangles. Yet the development of Alzheimer’s is not solely explained by amyloid and tau pathologies, Lah says.
"Two individuals may harbor similar amounts of amyloid plaques and tau tangles in their brains, but one may be completely healthy while the other may have severe memory loss and dementia," he says.
These discrepancies led Emory investigators to take a “back to basics” proteomics approach, cataloguing the proteins that make up insoluble deposits in the brains of Alzheimer’s patients.
"The Alzheimer’s field has been very focused on amyloid and tau, and we wanted to use today’s proteomics technologies to take a comprehensive, unbiased approach," Levey says.
The team identified 36 proteins that were much more abundant in the detergent-resistant deposits in brain tissue from Alzheimer’s patients. This list included the usual suspects: tau and beta-amyloid. Also on the list were several “U1 snRNP” proteins, which are involved in RNA splicing.
These U1 proteins are normally seen in the nucleus of normal cells, but in Alzheimer’s brains they accumulated in tangle-like structures. Accumulation of insoluble U1 protein was seen in samples from patients with mild cognitive impairment (MCI), a precursor stage to Alzheimer’s, but the U1 pathology was not seen in any other brain diseases that were examined.
According to Chad Hales, MD, PhD, one of the study’s lead authors, “U1 aggregation is occurring early in the disease, and U1 tangles can be seen independently of tau pathology. In some cases, we see accumulation of insoluble U1 proteins before the appearance of insoluble tau, suggesting that it is a very early event.”
For most genes, after RNA is read out from the DNA (transcription), some of the RNA must be spliced out. When brain cells accumulate clumps of U1 proteins, that could mean the process of splicing is impaired. To test this, the Emory team examined RNA from the brains of Alzheimer’s patients. In comparison to RNA from healthy brains, more of the RNA from Alzheimer’s brain samples was unspliced.
The finding could explain how many genes that have been linked to Alzheimer’s are having their effects. In cells, U1 snRNP plays multiple roles in processing RNA including the process of alternative splicing, by which one gene can make instructions for two or more proteins.
"U1 dysfunction might produce changes in RNA processing affecting many genes or specific changes affecting a few key genes that are important in Alzheimer’s," Lah says. "Understanding the disruption of such a fundamental process will almost certainly identify new ways to understand Alzheimer’s and new approaches to treating patients."
Faulty stem cell regulation may contribute to cognitive deficits associated with Down syndrome
The learning and physical disabilities that affect people with Down syndrome may be due at least in part to defective stem cell regulation throughout the body, according to researchers at the Stanford University School of Medicine. The defects in stem cell growth and self-renewal observed by the researchers can be alleviated by reducing the expression of just one gene on chromosome 21, they found.
The finding marks the first time Down syndrome has been linked to stem cells, and addresses some long-standing mysteries about the disorder. Although the gene, called Usp16, is unlikely to be the only contributor to the disease, the finding raises the possibility of an eventual therapy based on reducing its expression.
“There appear to be defects in the stem cells in all the tissues that we tested, including the brain,” said Michael Clarke, MD, Stanford’s Karel H. and Avice N. Beekhuis Professor in Cancer Biology. The researchers conducted their studies in both mouse and human cells. “We believe Usp16 overexpression is a major contributor to the neurological deficits seen in Down syndrome.”
Clarke is the senior author of the research, published Sept. 11 in Nature. Postdoctoral scholar Maddalena Adorno, PhD, is the lead author.
“Conceptually, this study suggests that drug-based strategies to slow the rate of stem cell use could have profound effects on cognitive function, aging and risk for Alzheimer’s disease in people with Down syndrome,” said co-author Craig Garner, PhD, who is the co-director of Stanford’s Center for Research and Treatment of Down Syndrome and a professor of psychiatry and behavioral sciences.
Down syndrome, which is caused by an extra copy of chromosome 21, affects about 400,000 people in the United States and 6 million worldwide. It causes both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function.
The new study’s findings suggest answers to many long-standing mysteries about the condition, including why people with Down syndrome appear to age faster and exhibit early Alzheimer’s disease.
“This study is the first to provide a possible explanation for these tendencies,” said Garner. The fact that people with Down syndrome have three copies of chromosome 21 and the Usp16 gene “accelerates the rate at which stem cells are used during early development, which likely exhausts stem cell pools and impairs tissue regeneration in adults with Down syndrome. As a result, their brains age faster and are susceptible to early onset neurodegenerative disorders.”
The researchers didn’t confine their studies to laboratory mice. They also investigated the effect of Usp16 overexpression in human cells. Adorno and colleagues in the laboratory of co-author Samuel Cheshier, MD, assistant professor of neurosurgery, found that the presence of excess Usp16 caused skin cells from unaffected people to grow more slowly. Furthermore, neural progenitor cells (those self-renewing cellular factories responsible for the development and maintenance of many of the cell types in the brain) were less able to form balls of cells called neurospheres — a laboratory test that reflects the number and robustness of nerve stem cells in a culture. Conversely, reducing Usp16 expression in skin and nerve-progenitor cells from people with Down syndrome allowed the cells, which usually proliferate slowly, to assume normal growth patterns.
“This gene is clearly regulating processes that are central to aging in mice and humans,” said Clarke, “and stem cells are severely compromised. Reducing Usp16 expression gives an unambiguous rescue at the stem cell level. The fact that it’s also involved in this human disorder highlights how critical stem cells are to our well-being.”
Adorno and Clarke didn’t set out to study Down syndrome. Clarke’s past research has focused on how normal stem cells and cancer stem cells regenerate themselves, and Adorno was searching for genes that could inhibit a specific molecular pathway involved in the self-renewal of these cells. Understanding how normal stem cells regenerate themselves could help to repair tissue and organ damage from disease, and understanding how cancer stem cells maintain themselves could help explain why they are unusually resistant to chemotherapy or radiation therapy — often resulting in a patient’s relapse after seemingly successful treatment. Usp16 seemed to fit the bill; it plays a critical role in a self-renewal pathway previously identified by Clarke and his colleagues.
But Adorno and Clarke soon realized that Usp16 had another interesting property: in humans, it is found on chromosome 21.
They turned to Garner and Cheshier to help them evaluate a possible link to Down syndrome. Garner supplied two strains of mice commonly used to study the condition. One, Ts65Dn, has three copies of 132 genes found on human chromosome 21 — including Usp16. The second, Ts1Cje, has three copies of 79 genes from the chromosome, but only two copies of Usp16. Although both mice display some symptoms of the disorder, Ts65Dn more closely mimics the craniofacial structure and learning and memory disabilities seen in affected humans.
Colleagues in the Cheshier laboratory found that neural stem cells from the more-severely affected Ts65Dn mice were less able to self-renew and grow normally than were cells from the Ts1Cje mice. Reducing the expression of Usp16 in the cells from the Ts65Dn mice to more normal levels largely corrected these functional defects.
“We demonstrated that central nervous system stem cells in Down syndrome mice were defective in their ability to self-renew — the process by which stem cells regenerate themselves upon cell division. Blocking Usp16 expression in these cells restored this ability,” said Cheshier. “We hope in the future that correcting this Usp16 defect can lead to therapeutics that will ameliorate the central nervous system defects seen in patients with Down syndrome.”
Finally, the researchers created a new, Ts65Dn-derived mouse strain in which one of the three copies of Usp16 was mutated. This normalized the level of expression of that gene, without affecting the overexpression of the other 131 triplicated genes in these mice. Nerve progenitor cells from these mice were equally able as normal cells to form neurospheres. The researchers are now continuing their studies of these mice.
“We are really interested in learning how other genes in this chromosomal region may be affecting stem cell renewal,” said Clarke. “We also want to understand how much we’re able to rescue the neurological defect by normalizing the expression of Usp16 in this mouse model. How does this compare to what is happening in humans? We’re sure it plays some significant role.”
(Source: med.stanford.edu)
Brain circuitry loss may be a very early sign of cognitive decline in healthy elderly people
The degeneration of a small, wishbone-shaped structure deep inside the brain may provide the earliest clues to future cognitive decline, long before healthy older people exhibit clinical symptoms of memory loss or dementia, a study by researchers with the UC Davis Alzheimer’s Disease Center has found.
The longitudinal study found that the only discernible brain differences between normal people who later developed cognitive impairment and those who did not were changes in their fornix, an organ that carries messages to and from the hippocampus, and that has long been known to play a role in memory.
“This could be a very early and useful marker for future incipient decline,” said Evan Fletcher, the study’s lead author and a project scientist with the UC Davis Alzheimer’s Disease Center.
“Our results suggest that fornix variables are measurable brain factors that precede the earliest clinically relevant deterioration of cognitive function among cognitively normal elderly individuals,” Fletcher said.
The research is published online today in JAMA Neurology.
Hippocampal atrophy occurs in the later stages of cognitive decline and is one of the most studied changes associated with the Alzheimer’s disease process. However, changes to the fornix and other regions of the brain structurally connected to the hippocampus have not been as closely examined. The study found that degeneration of the fornix in relation to cognition was detectable even earlier than changes in the hippocampus.
“Although hippocampal measures have been studied much more deeply in relation to cognitive decline, our direct comparison between fornix and hippocampus measures suggests that fornix properties have a superior ability to identify incipient cognitive decline among healthy individuals,” Fletcher said.
The study was conducted over five years in a group of 102 diverse, cognitively normal people with an average age of 73 who were recruited through community outreach at the Alzheimer’s Disease Center. The researchers conducted magnetic resonance imaging (MRI) studies of the participants’ brains that described their volumes and integrity. A different type of MRI was used to determine the integrity of the myelin, the fatty coating that sheaths and protects the axons. The axons are analogous to the copper wiring of the brain’s circuitry and the myelin is like the wiring’s plastic insulation.
Either one of those things being lost will “degrade the signal transmission” in the brain, Fletcher said.
The researchers also conducted psychological tests and cognitive evaluations of the study participants to gauge their level of cognitive functioning. The participants returned for updated MRIs and cognitive testing at approximately one-year intervals. At the outset, none of the study participants exhibited symptoms of cognitive decline. Over time about 20 percent began to show symptoms that led to diagnoses with either mild cognitive impairment (MCI) and, in a minority of cases, Alzheimer’s disease.
“We found that if you looked at various brain factors there was one — and only one — that seemed to be predictive of whether a person would have cognitive decline, and that was the degradation of the fornix,” Fletcher said.
The study measured two relevant fornix characteristics predicting future cognitive impairment — low fornix white matter volume and reduced axonal integrity. Each of these was stronger than any other brain factor in models predicting cognitive loss, Fletcher said.
He said that routine MRI examination of the fornix could conceivably be used clinically in the future as a predictor of abnormal cognitive decline.
“Our findings suggest that if your fornix volume or integrity is within a certain range you’re at an increased risk of cognitive impairment down the road. But developing the use of the fornix as a predictor in a clinical setting will take some time, in the same way that it took time for evaluation of cholesterol levels to be used to predict future heart disease,” he said.
Fletcher also said that the finding may mark a paradigm shift toward evaluation of the brain’s white matter, rather than its gray matter, as among the very earliest indicators of developing cognitive loss. There is currently a strong research focus on understanding brain processes that lead eventually to Alzheimer’s disease. He said the current finding could fill in one piece of the picture and motivate new directions in research to understand why and how fornix and other white matter change is such an important harbinger of cognitive impairment.
“The key importance of this finding is that it suggests that white matter tract measures may prove to be promising candidate biomarkers for predicting incipient cognitive decline among cognitively normal individuals in a clinical setting, possibly more so than gray matter measures,” he said.
(Source: ucdmc.ucdavis.edu)
Salk scientists and colleagues discover important mechanism underlying Alzheimer’s disease
Details of destructive neuronal pathway should help improve drug therapies
Alzheimer’s disease affects more than 26 million people worldwide. It is predicted to skyrocket as boomers age—nearly 106 million people are projected to have the disease by 2050. Fortunately, scientists are making progress towards therapies. A collaboration among several research entities, including the Salk Institute and the Sanford-Burnham Medical Research Institute, has defined a key mechanism behind the disease’s progress, giving hope that a newly modified Alzheimer’s drug will be effective.
In a previous study in 2009, Stephen F. Heinemann, a professor in Salk’s Molecular Neurobiology Laboratory, found that a nicotinic receptor called Alpha7 may help trigger Alzheimer’s disease. “Previous studies exposed a possible interaction between Alpha-7 nicotinic receptors (α7Rs) with amyloid beta, the toxic protein found in the disease’s hallmark plaques,” says Gustavo Dziewczapolski, a staff researcher in Heinemann’s lab. “We showed for the first time, in vivo, that the binding of this two proteins, α7Rs and amyloid beta, provoke detrimental effects in mice similar to the symptoms observed in Alzheimer’s disease .”
Their experiments, published in The Journal of Neuroscience, with Dziewczapolski as first author, consisted in testing Alzheimer’s disease-induced mice with and without the gene for α7Rs. They found that while both types of mice developed plaques, only the ones with α7Rs showed the impairments associated with Alzheimer’s.
But that still left a key question: Why was the pairing deleterious?
In a recent paper in the Proceedings of the National Academy of Sciences, Heinemann and Dziewczapolski here at Salk with Juan Piña-Crespo, Sara Sanz-Blasco, Stuart A. Lipton of the Sanford-Burnham Medical Research Institute and their collaborators announced they had found the answer in unexpected interactions among neurons and other brain cells.
Neurons communicate by sending electrical and chemical signals to each other across gaps called synapses. The biochemical mix at synapses resembles a major airport on a holiday weekend—it’s crowded, complicated and exquisitely sensitive to increases and decreases in traffic. One of these signaling chemicals is glutamate, an excitatory neurotransmitter, which is essential for learning and storing memories. In the right balance, glutamate is part of the normal functioning of neuronal synapses. But neurons are not the only cells in the brain capable of releasing glutamate. Astrocytes, once thought to be merely cellular glue between neurons, also release this neurotransmitter.
In this new understanding of Alzheimer’s disease, there is a cellular signaling cascade, in which amyloid beta stimulates the alpha 7 nicotine receptors, which trigger astrocytes to release additional glutamate into the synapse, overwhelming it with excitatory (“go”) signals.
This release in turn activates another set of receptors outside of the synapse, called extrasynaptic-N-methyl-D-aspartate receptors (eNMDARs) that depress synaptic activity. Unfortunately, the eNMDARs seem to overly depress synaptic function, leading to the memory loss and confusion associated with Alzheimer’s.
Now that the team has finally determined the steps in this destructive pathway, the good news is that a drug developed by the Lipton’s Laboratory called NitroMemantine, a modification of the earlier Alzheimer’s medication, Memantine, may block the entry of eNMDARs into the cascade.
"Thanks to the joint effort of our colleagues and collaborators, we seem to finally have a clear mechanistic link between a key target of the amyloid beta in the brain, the Alpha7 nicotinic receptors, triggering downstream harmful effects associated with the initiation and progression of Alzheimer’s disease," says Dziewczapolski. "This is a clear demonstration of the value of basic biomedical research. Drug development cannot proceed without knowing the details of interactions at the molecular and cellular level. Our research revealed two potential targets, α7Rs and eNMDARs, for future disease-modifying therapeutics, which Dr. Heinemann and I both hope will translate in a better treatment for Alzheimer’s patients."
(Source: salk.edu)
Stress-related protein speeds progression of Alzheimer’s disease
A stress-related protein genetically linked to depression, anxiety and other psychiatric disorders contributes to the acceleration of Alzheimer’s disease, a new study led by researchers at the University of South Florida has found.
The study is published online today in the Journal of Clinical Investigation.
When the stress-related protein FKBP51 partners with another protein known as Hsp90, this formidable chaperone protein complex prevents the clearance from the brain of the toxic tau protein associated with Alzheimer’s disease.
Under normal circumstances, tau helps make up the skeleton of our brain cells. The USF study was done using test tube experiments, mice genetically engineered to produce abnormal tau protein like that accumulated in the brains of people with Alzheimer’s disease, and post-mortem human Alzheimer’s brain tissue.
The researchers report that FKBP51 levels increase with age in the brain, and then the stress-related protein partners with Hsp90 to make tau more deadly to the brain cells involved in memory formation.
Hsp90 is a chaperone protein, which supervises the activity of tau inside nerve cells. Chaperone proteins typically help ensure that tau proteins are properly folded to maintain the healthy structure of nerve cells.
However, as FKBP51 levels rise with age, they usurp Hsp90’s beneficial effect to promote tau toxicity.
“We found that FKB51 commandeers Hsp90 to create an environment that prevents the removal of tau and makes it more toxic,” said the study’s principal investigator Chad Dickey, PhD, associate professor of molecular medicine at the USF Health Byrd Alzheimer’s Institute. “Basically, it uses Hsp90 to produce and preserve the bad tau.”
The researchers conclude that developing drugs or other ways to reduce FKB51 or block its interaction with Hsp90 may be highly effective in treating the tau pathology featured in Alzheimer’s disease, Parkinson’s disease dementia and several other disorders associated with memory loss.
A previous study by Dr. Dickey and colleagues found that a lack of FKBP51 in old mice improved resilience to depressive behavior.