Posts tagged dementia
Posts tagged dementia
Do fruit flies hold the key to treating dementia? Researchers at the University of Houston (UH) have taken a significant step forward in unraveling the mechanisms of Pavlovian conditioning. Their work will help them understand how memories form and, ultimately, provide better treatments to improve memory in all ages.
Gregg Roman, an associate professor of biology and biochemistry at UH, and Shixing Zhang, his postdoctoral associate, describe their findings in a paper titled “Presynaptic Inhibition of Gamma Lobe Neurons Is Required for Olfactory Learning in Drosophila,” appearing Nov. 27 in Current Biology, a scientific bimonthly journal published by Cell Press.
“Memory is essential to our daily function and is also central to our sense of self,” Roman said. “To a large degree, we are the sum of our experiences. When memories can no longer be retrieved or we have difficulty in forming new memories, the effects are frequently tragic. In the future, our work will enable us to have a better understanding of how human memories form.”
Roman and Zhang set about to unravel some of these mysteries by studying the brains of fruit flies (Drosophila). Within the fly brain, Roman says, there are nerve cells that play a role in olfactory learning and memory. Olfactory learning, he says, is an example of classical conditioning first described by Pavlov in his experiment with dogs. In their study, the flies were trained to associate a weak electric shock with an odor. After training, the flies avoided that odor.
“We found that these particular nerve cells – the gamma lobe neurons of the mushroom bodies in the insect brain – are activated by odors. Training the flies to associate an odor with an electric shock changed how these cells responded to odors by developing a modification in gamma lobe neuron activity, known as a memory trace,” he said. “Interestingly, we found that training caused the gamma lobe neurons to be more weakly activated by odors that were not paired with an electric shock, while the odors paired with electric shock maintained a strong activation of these neurons. Thus, the gamma lobe neurons responded more strongly to the trained odor than to the untrained odor.”
The team also showed that a specific protein – the heterotrimeric G(o) protein – is naturally involved in inhibiting gamma lobe neurons. Roman says removing the activity of this protein only within the gamma lobe neurons resulted in a loss of the memory trace and, thus, poor learning. Therefore, inhibiting the release of neurotransmitters from these neurons through the actions of the G(o) protein is key to forming the memory trace and associative memories.
The significance of using fruit flies is that while their brain structure is much simpler with far fewer neurons, the mushroom body is analogous to the perirhinal cortex in humans, which serves the same function of sensory integration and learning. This simplicity allows scientists to gain insights into how memories are acquired, stored and retrieved.
“Drosophila represents the Goldilocks principle of neural research, with sufficient behavioral complexity, while maintaining a huge advantage in neural simplicity,” Roman said. “The complex behaviors allow us to examine many behavioral processes like learning, attention, aggression and addiction-like behaviors, while the simplicity allows us to dissect the crucial neural activities down to single cells. Additionally, Drosophila has the most powerful genetic toolkit available for behavioral experimentation. In using these tools, we are genetically identifying the molecules necessary to perform these behaviors and dissecting the logic of the neural circuits that allow for changes in behavior to occur.”
The pair says all their experience to date suggests the molecules and logic will translate to most animals, including humans, leading to a more complete understanding of how memories form in humans, both at the level of molecules and through the activity of neural circuits.
Carrying a particular version of the gene for apolipoprotein E (APOE) is the major known genetic risk factor for the sporadic, late-onset form of Alzheimer’s disease, but exactly how that variant confers increased risk has been controversial among researchers. Now an animal study led by Massachusetts General Hospital (MGH) investigators shows that even low levels of the Alzheimer’s-associated APOE4 protein can increase the number and density of amyloid beta (A-beta) brain plaques, characteristic neuronal damage, and the amount of toxic soluble A-beta within the brain in mouse models of the disease. Introducing APOE2, a rare variant that has been associated with protection from developing Alzheimer’s disease, into the brains of animals with established plaques actually reduced A-beta deposition, retention and neurotoxicity, suggesting the potential for gene-therapy-based treatment.
"Using a technique developed by our collaborators at the University of Iowa, we were able to get long-term expression of these human gene variants in the fluid that bathes the entire brain," says Bradley Hyman, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), senior author of the report in the Nov. 20 Science Translational Medicine. “Our results suggest that strategies aimed at decreasing levels of APOE4, the harmful form of the protein, and increasing concentrations of protective variant APOE2 could be helpful to patients.”
The association between the APOE4 variant and increased Alzheimer’s risk was first made more than 20 years ago. Subsequent research has established that carrying two copies of the harmful variant increases risk 12 times compared with having two copies of the more common form, APOE3. Inheriting the APOE2 variant, however, appears to cut the risk in half. The extremely rare gene variants that directly cause the familial forms of the disease all participate in the production and deposition of A-beta, but exactly how APOE variants contribute to the process has been poorly understood.
Secreted by certain brain cells, APOE is known to regulate cholesterol metabolism within the brain and can bind to A-beta peptides, suggesting that the different forms of the protein may affect whether and how toxic A-beta plaques form. While previous investigations into the protein’s effects have used either mice in which gene expression was knocked out or transgenic animals that expressed human gene variants throughout their lifetimes, the MGH-MIND-led study used a different approach to investigate the effects of introducing the variant forms of the protein into brains in which plaque formation had already begun. They directly injected into the cerebrospinal fluid of a mouse model of Alzheimer’s – adult animals in which plaques were well established – viral vectors carrying genes for one of the three APOE variants or a control protein.
Two month after the vectors had been injected, about 10 percent of the APOE in the brains of animals that received one of the variants was found to be the introduced human version. At five months after injection, examination of brain tissue revealed that the A-beta plaques in mice that received APOE4 injections were more numerous and significantly denser than those of mice receiving APOE2. The growth of plaques in animals receiving APOE3 was intermediate between that of the other two groups and similar to what was seen in control animals. Levels of A-beta in the blood of mice that received APOE2 were higher than in the other groups, suggesting that the protective variant had increased clearance of A-beta from the brain.
In a group of animals in which tiny implanted windows allowed direct imaging of brain tissue, the progression of A-beta plaque deposition was fastest in animals receiving APOE4 and slowest, sometimes even appearing to regress, in mice injected with APOE2. Signs of neuronal damage around plaques also varied depending on the APOE variant the animals received, and experiments in a different Alzheimer’s model in which plaques appear more slowly showed that injection of APOE4 increased levels of free, soluble A-beta in the fluid that bathes the brain.
"This study has allowed us to sort out, in mice, which effects of the different types of APOE were most important to variation in amyloid plaque deposition," says Eloise Hudry, PhD, of MGH-MIND, lead author of the Science Translational Medicine report. “Our results imply that APOE-based therapeutic approaches may help to alleviate the progression of Alzheimer’s disease. More study is needed to pursue that possibility and to investigate the potential use of this gene transfer technology to introduce other protective proteins into the brain.”
The novel compound IRL-1620 may be useful in treating Alzheimer’s disease (AD) as it has been shown to prevent cognitive impairment and oxidative stress in animal models. This research is being presented at the 2013 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, the world’s largest pharmaceutical sciences meeting, in San Antonio, Nov. 10–14.
AD is a form of dementia that worsens over time, leading to a slow decline in cognitive functions and affecting memory, thinking, and behavior. More than 5 million Americans are living with AD, according to the Alzheimer’s Association.
Anil Gulati, M.D., Ph.D., FCP, and Seema Briyal, Ph.D., along with their colleagues from Midwestern University, administered Amyloid beta (Aβ), a main component of certain deposits located in AD patients’ brains, to normal and diabetic rats on days 1, 7, and 14. Spatial learning and memory were tested in a Morris water maze. The pool was divided into four equal quadrants, and an escape platform was hidden below the surface at a fixed location in one of the quadrants.
The rats had to find the platform within 60 seconds. The average time it took on day 4 for Aβ-treated rats to locate the platform was 55.05 seconds, though a majority of this group was not able to find it in the designated time. Aβ rats treated with IRL-1620 were able to locate the platform in 26.53 seconds, nearly half the time. After five days, Aβ rats treated with IRL-1620 showed a 60 percent improvement in learning and memory.
“Our research is based on the idea of using the Endothelin (ET) system in the treatment of AD,” said Gulati. “The ET system is traditionally known to play a role in the regulation of blood flow. This is important in the potential treatment of AD since disturbances in blood flow could damage the brain’s ability to clear damaging particles, leading to a build-up of toxic substances and cognitive impairment.”
The next stage of Gulati’s research is to further investigate the endothelin receptor type B’s mechanisms of neuroprotection and to look into possible resulting tissue changes following AD.
The FDA has approved five medications to treat the symptoms of AD. Current drugs help mask the symptoms but do not treat the underlying disease. A breakthrough Alzheimer’s treatment would target the underlying disease and stop or delay the cell damage that eventually leads to the worsening of symptoms.
People in middle age who have a high blood pressure measure called pulse pressure are more likely to have biomarkers of Alzheimer’s disease in their spinal fluid than those with lower pulse pressure, according to research published in the November 13, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
Pulse pressure is the systolic pressure, or the top number in a blood pressure reading, minus the diastolic, or the bottom number. Pulse pressure increases with age and is an index of the aging of the vascular system.
The study involved 177 people ages 55 to 100 with no symptoms of Alzheimer’s disease. Participants had their pulse pressure taken and lumbar punctures to obtain spinal fluid.
The study found that people who have higher pulse pressure are more likely to have the Alzheimer’s biomarkers amyloid beta, or plaques, and p-tau protein, or tangles, in their cerebral spinal fluid than those with lower pulse pressure. For every 10 point rise in pulse pressure, the average level of p-tau protein in the spinal fluid rose by 1.5 picograms per millileter. A picogram is one trillionth of a gram.
“These results suggest that the forces involved in blood circulation may be related to the development of the hallmark Alzheimer’s disease signs that cause loss of brain cells,” said study author Daniel A. Nation, PhD, of the VA San Diego Healthcare System.
The relationship was found in people age 55 to 70, but not in people age 70 to 100.
“This is consistent with findings indicating that high blood pressure in middle age is a better predictor of later problems with memory and thinking skills and loss of brain cells than high blood pressure in old age,” Nation said.
A team of scientists led by researchers from the University of California, San Diego School of Medicine and Ludwig Institute for Cancer Research have identified a novel therapeutic approach for the most frequent genetic cause of ALS, a disorder of the regions of the brain and spinal cord that control voluntary muscle movement, and frontotemporal degeneration, the second most frequent dementia.
Published ahead of print in last week’s online edition of the journal PNAS, the study establishes using segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and selectively degrade the toxic RNA that contributes to the most common form of ALS, without affecting the normal RNA produced from the same gene.
The new approach may also have the potential to treat frontotemporal degeneration or frontotemporal dementia (FTD), a brain disorder characterized by changes in behavior and personality, language and motor skills that also causes degeneration of regions of the brain.
In 2011, scientists found that a specific gene known as C9orf72 is the most common genetic cause of ALS. It is a very specific type of mutation which, instead of changing the protein, involves a large expansion, or repeated sequence of a set of nucleotides – the basic component of RNA.
A normal C9orf72 gene contains fewer than 30 of the nucleotide repeat unit, GGGGCC. The mutant gene may contain hundreds of repeats of this unit, which generate a repeat containing RNA that the researchers show aggregate into foci.
“Remarkably, we found two distinct sets of RNA foci, one containing RNAs transcribed in the sense direction and the other containing anti-sense RNAs,” said first author Clotilde Lagier-Tourenne, MD, PhD, UC San Diego Department of Neurosciences and Ludwig Institute for Cancer Research.
The researchers also discovered a signature of changes in expression of other genes that accompanies expression of the repeat-containing RNAs. Since they found that reducing the level of expression of the C9orf72 gene in a normal adult nervous system did not produce this signature of changes, the evidence demonstrated a toxicity of the repeat-containing RNAs that could be relieved by reducing the levels of those toxic RNAs.
“This led to our use of the ASOs to target the sense strand. We reduced the accumulation of expanded RNA foci and corrected the sense strand of the gene. Importantly, we showed that we could remove the toxic RNA without affecting the normal RNA that encodes the C9orf72 protein. This selective silencing of a toxic RNA is the holy grail of gene silencing approaches, and we showed we had accomplished it,” Lagier-Tourenne added.
Targeting the sense strand RNAs with a specific ASO did not, however, affect the antisense strand foci nor did it correct the signature of gene expression changes. “Doing that will require separate targeting of the antisense strand – or both - and has now become a critical question,“ Lagier-Tourenne said.
“This approach is exciting as it links two neurodegenerative diseases, ALS and FTD, to the field of expansion, which has gained broadened interest from investigators,” said co-principal investigator John Ravits, MD, UC San Diego Department of Neurosciences. “At the same time, our study also demonstrates the – to now – unrecognized role of anti-sense RNA and its potential as a therapeutic target.”
A Columbia University Medical Center-led research team has clinically validated a new method for predicting time to full-time care, nursing home residence, or death for patients with Alzheimer’s disease. The method, which uses data gathered from a single patient visit, is based on a complex model of Alzheimer’s disease progression that the researchers developed by consecutively following two sets of Alzheimer’s patients for 10 years each. The results were published online ahead of print in the Journal of Alzheimer’s Disease.
“Predicting Alzheimer’s progression has been a challenge because the disease varies significantly from one person to another—two Alzheimer’s patients may both appear to have mild forms of the disease, yet one may progress rapidly, while the other progresses much more slowly,” said senior author Yaakov Stern, PhD, professor of neuropsychology (in neurology, psychiatry, and psychology and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center) at CUMC. “Our method enables clinicians to predict the disease path with great specificity.”
A team of scientists examined almost 650 dementia patients and assessed when each one had been diagnosed with the condition. The study was carried out by researchers from the University and Nizam’s Institute of Medical Sciences in Hyderabad (India).
They found that people who spoke two or more languages experienced a later onset of Alzheimer’s disease, vascular dementia and frontotemporal dementia.
The bilingual advantage extended to illiterate people who had not attended school. This confirms that the observed effect is not caused by differences in formal education.
It is the largest study so far to gauge the impact of bilingualism on the onset of dementia - independent of a person’s education, gender, occupation and whether they live in a city or in the country, all of which have been examined as potential factors influencing the onset of dementia.
Natural brain training
The team of researchers say further studies are needed to determine the mechanism, which causes the delay in the onset of dementia. The researchers suggest that bilingual switching between different sounds, words, concepts, grammatical structures and social norms constitutes a form of natural brain training, likely to be more effective than any artificial brain training programme.
However, studies of bilingualism are complicated by the fact that bilingual populations are often ethnically and culturally different from monolingual societies. India offers in this respect a unique opportunity for research. In places like Hyderabad, bilingualism is part of everyday life: knowledge of several languages is the norm and monolingualism an exception.
These findings suggest that bilingualism might have a stronger influence on dementia that any currently available drugs. This makes the study of the relationship between bilingualism and cognition one of our highest priorities. -Thomas Bak, School of Philosophy, Psychology and Language Sciences
The study, published in Neurology, the medical journal of the American Academy of Neurology, was supported by the Indian Department of Science and Technology and by the Centre for Cognitive Aging and Cognitive Epidemiology (CCACE) at the University of Edinburgh. It was led by Suvarna Alladi, DM, at the Nizam’s Institute of Medical Sciences in Hyderabad.
For the first time in a large study sample, the decline in brain function in normal aging is conclusively shown to be influenced by genes, say researchers from the Texas Biomedical Research Institute and Yale University.
“Identification of genes associated with brain aging should improve our understanding of the biological processes that govern normal age-related decline,” said John Blangero, Ph.D., a Texas Biomed geneticist and the senior author of the paper. The study, funded by the National Institutes of Health (NIH), is published in the November 4, 2013 issue of the Proceedings of the National Academy of Sciences. David Glahn, Ph.D., an associate professor of psychiatry at the Yale University School of Medicine, is the first author on the paper.
In large pedigrees including 1,129 people aged 18 to 83, the scientists documented profound aging effects from young adulthood to old age, on neurocognitive ability and brain white matter measures. White matter actively affects how the brain learns and functions. Genetic material shared amongst biological relatives appears to predict the observed changes in brain function with age.
Participants were enrolled in the Genetics of Brain Structure and Function Study and drawn from large Mexican Americans families in San Antonio. Brain imaging studies were conducted at the University of Texas Health Science Center at San Antonio Research Imaging Institute directed by Peter Fox, M.D.
“The use of large human pedigrees provides a powerful resource for measuring how genetic factors change with age,” Blangero said.
By applying a sophisticated analysis, the scientists demonstrated a heritable basis for neurocognitive deterioration with age that could be attributed to genetic factors. Similarly, decreasing white matter integrity with age was influenced by genes., The investigators further demonstrated that different sets of genes are responsible for these two biological aging processes.
“A key advantage of this study is that we specifically focused on large extended families and so we were able to disentangle genetic from non-genetic influences on the aging process,” said Glahn.
Scientists have known for some time that a protein called presenilin plays a role in Alzheimer’s disease, and a new study reveals one intriguing way this happens.
It has to do with how materials travel up and down brain cells, which are also called neurons.
In an Oct. 8 paper in Human Molecular Genetics, University at Buffalo researchers report that presenilin works with an enzyme called GSK-3ß to control how fast materials — like proteins needed for cell survival — move through the cells.
“If you have too much presenilin or too little, it disrupts the activity of GSK-3ß, and the transport of cargo along neurons becomes uncoordinated,” says lead researcher Shermali Gunawardena, PhD, an assistant professor of biological sciences at UB. “This can lead to dangerous blockages.”
More than 150 mutations of presenilin have been found in Alzheimer’s patients, and scientists have previously shown that the protein, when defective, can cause neuronal blockages by snipping another protein into pieces that accumulate in brain cells.
But this well-known mechanism isn’t the only way presenilin fuels disease, as Gunawardena’s new study shows.
“Our work elucidates how problems with presenilin could contribute to early problems observed in Alzheimer’s disease,” she says. “It highlights a potential pathway for early intervention through drugs — prior to neuronal loss and clinical manifestations of disease.”
The study suggests that presenilin activates GSK-3ß. This is an important finding because the enzyme helps control the speed at which tiny, organic bubbles called vesicles ferry cargo along neuronal highways. (You can think of vesicles as trucks, each powered by little molecular motors called dyneins and kinesins.)
When researchers lowered the amount of presenilin in the neurons of fruit fly larvae, less GSK-3ß became activated and vesicles began speeding along cells in an uncontrolled manner.
Decreasing levels of both presenilin and GSK-3ß at once made things worse, resulting in “traffic jams” as the bubbles got stuck in neurons.
“Both GSK-3ß and presenilin have been shown to be involved in Alzheimer’s disease, but how they are involved has not always been clear,” Gunawardena says. “Our research provides new insight into this question.”
Gunawardena proposes that GSK-3ß — short for glycogen synthase kinase-3beta — acts as an “on switch” for dynein and kynesin motors, telling them when to latch onto vesicles.
Dyneins carry vesicles toward the cell nucleus, while kinesins move in the other direction, toward the periphery of the cell. When all is well and GSK-3ß levels are normal, both types of motors bind to vesicles in carefully calibrated numbers, resulting in smooth traffic flow along neurons.
That’s why it’s so dangerous when GSK-3ß levels are off-kilter, she says.
When GSK-3ß levels are high, too many motors attach to the vesicles, leading to slow movement as motor activity loses coordination. Low GSK-3ß levels appear to have the opposite effect, causing fast, uncontrolled movement as too few motors latch onto vesicles.
Both scenarios — too much GSK-3ß or too little — can result in neuronal blockages.
An international group of researchers has identified 11 new genes that offer important new insights into the disease pathways involved in Alzheimer’s disease. The highly collaborative effort involved scanning the DNA of over 74,000 volunteers—the largest genetic analysis yet conducted in Alzheimer’s research—to discover new genetic risk factors linked to late-onset Alzheimer’s disease, the most common form of the disorder.
By confirming or suggesting new processes that may influence Alzheimer’s disease development—such as inflammation and synaptic function—the findings point to possible targets for the development of drugs aimed directly at prevention or delaying disease progression.
Supported in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health, the International Genomic Alzheimer’s Project (IGAP) reported its findings online in Nature Genetics on Oct. 27, 2013. IGAP is comprised of four consortia in the United States and Europe which have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared datasets. GWAS are aimed at detecting the subtle gene variants involved in Alzheimer’s and defining how the molecular mechanisms influence disease onset and progression.
"Collaboration among researchers is key to discerning the genetic factors contributing to the risk of developing Alzheimer’s disease," said Richard J. Hodes, M.D., director of the NIA. "We are tremendously encouraged by the speed and scientific rigor with which IGAP and other genetic consortia are advancing our understanding."
The search for late-onset Alzheimer’s risk factor genes had taken considerable time, until the development of GWAS and other techniques. Until 2009, only one gene variant, Apolipoprotein E-e4 (APOE-e4), had been identified as a known risk factor. Since then, prior to today’s discovery, the list of known gene risk factors had grown to include other players—PICALM, CLU, CR1, BIN1, MS4A, CD2AP, EPHA1, ABCA7, SORL1 and TREM2.
IGAP’s discovery reported today of 11 new genes strengthens evidence about the involvement of certain pathways in the disease, such as the role of the SORL1 gene in the abnormal accumulation of amyloid protein in the brain, , a hallmark of Alzheimer’s disease. It also offers new gene risk factors that may influence several cell functions, to include the ability of microglial cells to respond to inflammation.
The researchers identified the new genes by analyzing previously studied and newly collected DNA data from 74,076 older volunteers with Alzheimer’s and those free of the disorder from 15 countries. The new genes (HLA-DRB5/HLA0DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2 and CASS4) add to a growing list of gene variants associated with onset and progression of late-onset Alzheimer’s. Researchers will continue to explore the roles played by these genes, to include:
The study also brought to light another 13 variants that merit further analysis.
"Interestingly, we found that several of these newly identified genes are implicated in a number of pathways," said Gerard Schellenberg, Ph.D., University of Pennsylvania School of Medicine, Philadelphia, who directs one of the major IGAP consortia. "Alzheimer’s is a complex disorder, and more study is needed to determine the relative role each of these genetic factors may play. I look forward to our continued collaboration to find out more about these—and perhaps other—genes."
(Image: National Institute on Aging)