Diabetes and dementia are rising dramatically in the United States and worldwide. In the last few years, epidemiological data has accrued showing that older people with diabetes are significantly more likely to develop cognitive deterioration and increased susceptibility to onset of dementia related to Alzheimer's disease. Now, a research team led by Giulio Maria Pasinetti, MD, PhD, the Saunders Family Chair and Professor of Neurology at the Icahn School of Medicine at Mount Sinai, discovered a novel mechanism through which this may occur. The results are published online in the journal Diabetes.
Dr. Pasinetti and colleagues pinpointed changes in post-mortem brains of human subjects. They reported that gene expression was dysfunctional in the brains of diabetic human subjects, and this increase was associated with reduced expression of important molecules that play a critical role in maintaining the structural integrity of brain regions associated with learning.
Excited by this finding, Dr. Pasinetti reasoned that if the hypothesis was correct, similar conditions should be repeated in the laboratory by inducing diabetes in mice genetically predisposed to developing Alzheimer's type memory deterioration.
In fact, Dr. Pasinetti's laboratory confirmed this prediction in the mouse model, supporting the hypothesis that diabetes, through epigenetic changes in the brain, may casually promote onset and progression of Alzheimer's disease. Epigenetic changes are chemical changes in DNA that effect gene expression, but don't alter the actual genetic code.
"This new evidence is extremely intriguing, given that approximately 60 percent of Alzheimer's disease patients have at least one serious medical condition associated with diabetes," said Dr. Pasinetti. "What this adds is much needed insight into the potential mechanism that might explain the relationship between diabetes and Alzheimer's disease onset and progression by mechanisms through which DNA functions."
The discovery in Dr. Pasinetti's laboratory has staggering societal implications. More than 5 million are affected by Alzheimer's disease dementia, and the disease incidence is expected to skyrocket in the three decades as the population ages.
"The next question we must ask is how we can translate this into the development of novel disease prevention and treatment strategies," Dr. Pasinetti added. "If we can find out how DNA epigenetic modification can be manipulated pharmacologically, these studies will be instrumental in the formulation of novel treatments and possible preventative strategies in Alzheimer's disease.
Thursday, January 9, 2014
How our brain resists temptation in preference of 'future rewards'
When on a strict diet, it can be very hard to resist a bar of chocolate if it is right under your nose. Are you likely to eat it there and then? Or wait until the end of the week to intensify the satisfying experience? Whatever your answer, researchers now say they can explain the difference in people's ability to resist temptation.
According to researchers from the Brain and Spine Institute in Paris, activity in the hippocampus of the brain - an area of the brain involved in forming, storing and organizing memories - is crucial in making the decision to delay rewards.
Previous studies have analyzed human's temporal choices, with researchers conducting brain scans while participants are asked to make monetary choices, such as $10 now or $11 tomorrow.
"However, these paradigms miss an essential feature of the inter-temporal conflicts we have to face in everyday life," says Dr. Mathias Pessiglione of the Brain and Spine Institute and leader of the study.
"[...] immediate rewards can be perceived through our senses, whereas future rewards must be represented in our imagination."
To reach their findings, published in the journal PLOS Biology, the researchers conducted a series of experiments on volunteers using more natural rewards that people come across in everyday life. For example, participants were asked if they would like a beer today, or a bottle of champagne in a week's time.
Imagining future rewards
The participants were presented with choices between immediate rewards that were presented as pictures, or future rewards that were presented as text, meaning participants had to "imagine" the long-term rewards.
The researchers found that the ability to select future rewards was linked to the amount of activity in the hippocampus.
They then conducted the same experiments on a group of patients with hippocampus damage as a result of Alzheimer's disease, alongside patients with behavioral variant of frontotemporal dementia (bvFTD) as a result of prefrontal cortex degeneration. The prefrontal cortex of the brain is known to implement behavioral control.
Results showed that those with bvFTD demonstrated high impulsiveness in all choices, but those with Alzheimer's disease showed more bias towards immediate rewards when long-term rewards had to be imagined.
Dr. Pessiglione says the reason for these results is because the hippocampus plays an important role in imagining future situations by building details that makes long-term rewards appear more attractive.
According to researchers from the Brain and Spine Institute in Paris, activity in the hippocampus of the brain - an area of the brain involved in forming, storing and organizing memories - is crucial in making the decision to delay rewards.
Previous studies have analyzed human's temporal choices, with researchers conducting brain scans while participants are asked to make monetary choices, such as $10 now or $11 tomorrow.
"However, these paradigms miss an essential feature of the inter-temporal conflicts we have to face in everyday life," says Dr. Mathias Pessiglione of the Brain and Spine Institute and leader of the study.
"[...] immediate rewards can be perceived through our senses, whereas future rewards must be represented in our imagination."
To reach their findings, published in the journal PLOS Biology, the researchers conducted a series of experiments on volunteers using more natural rewards that people come across in everyday life. For example, participants were asked if they would like a beer today, or a bottle of champagne in a week's time.
Imagining future rewards
The participants were presented with choices between immediate rewards that were presented as pictures, or future rewards that were presented as text, meaning participants had to "imagine" the long-term rewards.
The researchers found that the ability to select future rewards was linked to the amount of activity in the hippocampus.
They then conducted the same experiments on a group of patients with hippocampus damage as a result of Alzheimer's disease, alongside patients with behavioral variant of frontotemporal dementia (bvFTD) as a result of prefrontal cortex degeneration. The prefrontal cortex of the brain is known to implement behavioral control.
Results showed that those with bvFTD demonstrated high impulsiveness in all choices, but those with Alzheimer's disease showed more bias towards immediate rewards when long-term rewards had to be imagined.
Dr. Pessiglione says the reason for these results is because the hippocampus plays an important role in imagining future situations by building details that makes long-term rewards appear more attractive.
Researchers demonstrate preventive effect of sterols in Alzheimer's disease
Plant sterols are present in various combinations in nuts, seeds and plant oils. As plant sterols are the equivalents of animal cholesterol, they can in principal influence metabolic processes, where cholesterol is involved," explained Marcus Grimm, Head of the Experimental Neurology Laboratory at Saarland University. "Because they also lower cholesterol levels, they are extensively used in the food industry and as dietary supplements."
High cholesterol levels have long been discussed to increase the risk of developing Alzheimer's disease. "Studies have already shown that cholesterol promotes the formation of so-called senile plaques," said Grimm. These plaques, which are composed of proteins, particularly beta-amyloid proteins, deposit at nerve cells within the brain and are regarded as one of the main causes of Alzheimer's disease.
The research team based at Saarland University's medical campus in Homburg collaborated with scientists from Bonn, Finland and the Netherlands to examine how the sterols that we ingest influence the formation of these plaque proteins. It was found that one sterol in particular, stigmasterol, actually inhibited protein formation. "Stigmasterol has an effect on a variety of molecular processes: it lowers enzyme activity, it inhibits the formation of proteins implicated in the development of Alzheimer's disease, and it alters the structure of the cell membrane," explained Dr Grimm. "Together, these effects synergistically reduce the production of beta-amyloid proteins." The research team has been able to confirm the positive effect of stigmasterol in tests on animals.
Overall, the researchers were able to demonstrate that the various plant sterols influence different cellular mechanisms and therefore have to be assessed individually. "Particularly in the case of Alzheimer's disease, it seems expedient to focus on the dietary intake of specific plant sterols rather than a mixture of sterols," explained Dr Grimm. In future studies, the research team wants to determine which other cellular processes in the brain are affected by phytosterols.
High cholesterol levels have long been discussed to increase the risk of developing Alzheimer's disease. "Studies have already shown that cholesterol promotes the formation of so-called senile plaques," said Grimm. These plaques, which are composed of proteins, particularly beta-amyloid proteins, deposit at nerve cells within the brain and are regarded as one of the main causes of Alzheimer's disease.
The research team based at Saarland University's medical campus in Homburg collaborated with scientists from Bonn, Finland and the Netherlands to examine how the sterols that we ingest influence the formation of these plaque proteins. It was found that one sterol in particular, stigmasterol, actually inhibited protein formation. "Stigmasterol has an effect on a variety of molecular processes: it lowers enzyme activity, it inhibits the formation of proteins implicated in the development of Alzheimer's disease, and it alters the structure of the cell membrane," explained Dr Grimm. "Together, these effects synergistically reduce the production of beta-amyloid proteins." The research team has been able to confirm the positive effect of stigmasterol in tests on animals.
Overall, the researchers were able to demonstrate that the various plant sterols influence different cellular mechanisms and therefore have to be assessed individually. "Particularly in the case of Alzheimer's disease, it seems expedient to focus on the dietary intake of specific plant sterols rather than a mixture of sterols," explained Dr Grimm. In future studies, the research team wants to determine which other cellular processes in the brain are affected by phytosterols.
Scientists discover 11 new Alzheimer's risk genes
In what promises to be a major breakthrough in our understanding of Alzheimer's disease, an international group of scientists has discovered 11 previously unknown genes that increase people's risk of developing this most common cause of dementia.
The study, undertaken by the International Genomics Project (IGAP) and co-led by Cardiff University, Wales, UK, is published online this week in Nature Genetics.
The large group of four teams comes from 145 academic centers around the world and comprises most of the world's experts in the genetics of Alzheimer's.
They believe the discovery, which now brings the total number of genes known to raise the risk of developing Alzheimer's disease to 21, will open new avenues of research to improve our knowledge about the mechanisms that underpin the brain-wasting disease.
Prof. Julie Williams, head of neurodegeneration at Cardiff School of Medicine's Medical Research Council (MRC) Centre on Neuropsychiatric Genetics and Genomics, led one of the four international teams. She says:
"By combining the expertise and resources of geneticists across the globe, we have been able to overcome our natural competitive instincts to achieve a real breakthrough in identifying the genetic architecture that significantly contributes to our mapping of the disease."
The study builds on genome-wide association analysis work that, since 2009, has found the other 10 genes already known to be linked with Alzheimer's.
Prof. Williams, who is also chief scientific advisor for Wales, says the biggest surprise was finding out that several of the new genes involve the body's immune response in causing dementia.
However, she cautions that although we now have details of 21 genes known to increase risk of developing Alzheimer's, "a large portion of the genetic risk for the disease remains unexplained."
"Further research is still needed to locate the other genes involved before we can get a complete picture," she adds.
Discovery 'confirms' immune system's involvement
For the study, the teams gathered genome data from 74,076 people from 15 countries around the world to find the 11 new genes.
The researchers say one of the most significant findings relates to the HLA-DRB5/DRB1 major histocompatibility complex region of the genome. This discovery confirms that the immune system is somehow involved in the disease. This same region is associated with multiple sclerosis and Parkinson's disease.
The discoveries revolve around the most common, late-onset type of Alzheimer's.
Prof. Williams says they now want to turn their attention to people with the early-onset form of Alzheimer's, who get a more severe form of the disease in their 40s and 50s:
"Their genetic architecture may hold the key to finding yet more genes involved in Alzheimer's. They carry a heavier genetic load than people who develop the condition in later life and will yield clues about what genetic markers we should be looking out for."
She says they will also be bringing together what has been found out about environmental factors that increase and decrease the risk of developing Alzheimer's disease.
Prof. Williams says these discoveries are greatly helped by the fact experts in the genetics of Alzheimer's set aside their urge to compete and instead come together in the large teams that are necessary to make these kinds of breakthroughs. Now the same needs to happen with the biologists, she adds:
"It would be greatly encouraging to also see the world's molecular biologists all pulling together, breaking out of their silos and uniting in their aim of unraveling disease and developing the treatments to tackle it."
The research was partly funded by the Medical Research Council, the Welsh Government and Alzheimer's Research UK.
The study, undertaken by the International Genomics Project (IGAP) and co-led by Cardiff University, Wales, UK, is published online this week in Nature Genetics.
The large group of four teams comes from 145 academic centers around the world and comprises most of the world's experts in the genetics of Alzheimer's.
They believe the discovery, which now brings the total number of genes known to raise the risk of developing Alzheimer's disease to 21, will open new avenues of research to improve our knowledge about the mechanisms that underpin the brain-wasting disease.
Prof. Julie Williams, head of neurodegeneration at Cardiff School of Medicine's Medical Research Council (MRC) Centre on Neuropsychiatric Genetics and Genomics, led one of the four international teams. She says:
"By combining the expertise and resources of geneticists across the globe, we have been able to overcome our natural competitive instincts to achieve a real breakthrough in identifying the genetic architecture that significantly contributes to our mapping of the disease."
The study builds on genome-wide association analysis work that, since 2009, has found the other 10 genes already known to be linked with Alzheimer's.
Prof. Williams, who is also chief scientific advisor for Wales, says the biggest surprise was finding out that several of the new genes involve the body's immune response in causing dementia.
However, she cautions that although we now have details of 21 genes known to increase risk of developing Alzheimer's, "a large portion of the genetic risk for the disease remains unexplained."
"Further research is still needed to locate the other genes involved before we can get a complete picture," she adds.
Discovery 'confirms' immune system's involvement
For the study, the teams gathered genome data from 74,076 people from 15 countries around the world to find the 11 new genes.
The researchers say one of the most significant findings relates to the HLA-DRB5/DRB1 major histocompatibility complex region of the genome. This discovery confirms that the immune system is somehow involved in the disease. This same region is associated with multiple sclerosis and Parkinson's disease.
The discoveries revolve around the most common, late-onset type of Alzheimer's.
Prof. Williams says they now want to turn their attention to people with the early-onset form of Alzheimer's, who get a more severe form of the disease in their 40s and 50s:
"Their genetic architecture may hold the key to finding yet more genes involved in Alzheimer's. They carry a heavier genetic load than people who develop the condition in later life and will yield clues about what genetic markers we should be looking out for."
She says they will also be bringing together what has been found out about environmental factors that increase and decrease the risk of developing Alzheimer's disease.
Prof. Williams says these discoveries are greatly helped by the fact experts in the genetics of Alzheimer's set aside their urge to compete and instead come together in the large teams that are necessary to make these kinds of breakthroughs. Now the same needs to happen with the biologists, she adds:
"It would be greatly encouraging to also see the world's molecular biologists all pulling together, breaking out of their silos and uniting in their aim of unraveling disease and developing the treatments to tackle it."
The research was partly funded by the Medical Research Council, the Welsh Government and Alzheimer's Research UK.
The wrong levels of a protein linked with Alzheimer's disease can lead to dangerous blockages in brain cells
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 a paper in Human Molecular Genetics, University at Buffalo researchers report that presenilin works with an enzyme called GSK-3beta 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 -0 too much GSK-3ß or too little - can result in neuronal blockages.
It has to do with how materials travel up and down brain cells, which are also called neurons.
In a paper in Human Molecular Genetics, University at Buffalo researchers report that presenilin works with an enzyme called GSK-3beta 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 -0 too much GSK-3ß or too little - can result in neuronal blockages.
FDA approves second brain imaging drug to help evaluate patients for Alzheimer's disease, dementia
The U.S. Food and Drug Administration has approved Vizamyl (flutemetamol F 18 injection), a radioactive diagnostic drug for use with positron emission tomography (PET) imaging of the brain in adults being evaluated for Alzheimer's disease (AD) and dementia.
Dementia is associated with diminishing brain functions such as memory, judgment, language and complex motor skills. The dementia caused by AD is associated with the accumulation in the brain of an abnormal protein called beta amyloid and damage or death of brain cells. However, beta amyloid can also be found in the brain of patients with other dementias and in elderly people without neurologic disease.
Vizamyl works by attaching to beta amyloid and producing a PET image of the brain that is used to evaluate the presence of beta amyloid. A negative Vizamyl scan means that there is little or no beta amyloid accumulation in the brain and the cause of the dementia is probably not due to AD. A positive scan means that there is probably a moderate or greater amount of amyloid in the brain, but it does not establish a diagnosis of AD or other dementia. Vizamyl does not replace other diagnostic tests used in the evaluation of AD and dementia.
"Many Americans are evaluated every year to determine the cause of diminishing neurologic functions, such as memory and judgment, that raise the possibility of Alzheimer's disease," said Shaw Chen, M.D., deputy director of the Office of Drug Evaluation IV in the FDA's Center for Drug Evaluation and Research. "Imaging drugs like Vizamyl provide physicians with important tools to help evaluate patients for AD and dementia."
Vizamyl is the second diagnostic drug available for visualizing beta amyloid on a PET scan of the brain. In 2012, FDA approved Amyvid (Florbetapir F 18 injection) to help evaluate adults for AD and other causes of cognitive decline.
Vizamyl's effectiveness was established in two clinical studies comprised of 384 participants with a range of cognitive function. All participants were injected with Vizamyl and were scanned. The images were interpreted by five independent readers masked to all clinical information. A portion of scan results were also confirmed by autopsy.
The study results demonstrate that Vizamyl correctly detects beta amyloid in the brain. The results also confirm that the scans are reproducible and trained readers can accurately interpret the scans. Vizamyl's safety was established in a total of 761 participants.
Vizamyl is not indicated to predict the development of AD or to check how patients respond to treatment for AD. Vizamyl PET images should be interpreted only by health care professionals who successfully complete training in an image interpretation program. The Vizamyl drug labeling includes information about image interpretation.
Safety risks associated with Vizamyl include hypersensitivity reactions and the risks associated with image misinterpretation and radiation exposure. Common side effects associated with Vizamyl include flushing, headache, increased blood pressure, nausea and dizziness.
Vizamyl is manufactured for GE Healthcare by Medi-Physics, Inc., based in Arlington Heights, Ill.
Dementia is associated with diminishing brain functions such as memory, judgment, language and complex motor skills. The dementia caused by AD is associated with the accumulation in the brain of an abnormal protein called beta amyloid and damage or death of brain cells. However, beta amyloid can also be found in the brain of patients with other dementias and in elderly people without neurologic disease.
Vizamyl works by attaching to beta amyloid and producing a PET image of the brain that is used to evaluate the presence of beta amyloid. A negative Vizamyl scan means that there is little or no beta amyloid accumulation in the brain and the cause of the dementia is probably not due to AD. A positive scan means that there is probably a moderate or greater amount of amyloid in the brain, but it does not establish a diagnosis of AD or other dementia. Vizamyl does not replace other diagnostic tests used in the evaluation of AD and dementia.
"Many Americans are evaluated every year to determine the cause of diminishing neurologic functions, such as memory and judgment, that raise the possibility of Alzheimer's disease," said Shaw Chen, M.D., deputy director of the Office of Drug Evaluation IV in the FDA's Center for Drug Evaluation and Research. "Imaging drugs like Vizamyl provide physicians with important tools to help evaluate patients for AD and dementia."
Vizamyl is the second diagnostic drug available for visualizing beta amyloid on a PET scan of the brain. In 2012, FDA approved Amyvid (Florbetapir F 18 injection) to help evaluate adults for AD and other causes of cognitive decline.
Vizamyl's effectiveness was established in two clinical studies comprised of 384 participants with a range of cognitive function. All participants were injected with Vizamyl and were scanned. The images were interpreted by five independent readers masked to all clinical information. A portion of scan results were also confirmed by autopsy.
The study results demonstrate that Vizamyl correctly detects beta amyloid in the brain. The results also confirm that the scans are reproducible and trained readers can accurately interpret the scans. Vizamyl's safety was established in a total of 761 participants.
Vizamyl is not indicated to predict the development of AD or to check how patients respond to treatment for AD. Vizamyl PET images should be interpreted only by health care professionals who successfully complete training in an image interpretation program. The Vizamyl drug labeling includes information about image interpretation.
Safety risks associated with Vizamyl include hypersensitivity reactions and the risks associated with image misinterpretation and radiation exposure. Common side effects associated with Vizamyl include flushing, headache, increased blood pressure, nausea and dizziness.
Vizamyl is manufactured for GE Healthcare by Medi-Physics, Inc., based in Arlington Heights, Ill.
Specific molecules identified that could be targeted to treat Alzheimer's disease
Plaques and tangles made of proteins are believed to contribute to the debilitating progression of Alzheimer's disease. But proteins also play a positive role in important brain functions, like cell-to-cell communication and immunological response. Molecules called microRNAs regulate both good and bad protein levels in the brain, binding to messenger RNAs to prevent them from developing into proteins.
Now, Dr. Boaz Barak and a team of researchers in the lab of Prof. Uri Ashery of Tel Aviv University's Department of Neurobiology at the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience have identified a specific set of microRNAs that detrimentally regulate protein levels in the brains of mice with Alzheimer's disease and beneficially regulate protein levels in the brains of other mice living in a stimulating environment.
"We were able to create two lists of microRNAs - those that contribute to brain performance and those that detract - depending on their levels in the brain," says Dr. Barak. "By targeting these molecules, we hope to move closer toward earlier detection and better treatment of Alzheimer's disease."
Prof. Daniel Michaelson of TAU's Department of Neurobiology in the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience, Dr. Noam Shomron of TAU's Department of Cell and Developmental Biology and Sagol School of Neuroscience, Dr. Eitan Okun of Bar-Ilan University, and Dr. Mark Mattson of the National Institute on Aging collaborated on the study, published in Translational Psychiatry.
A double-edged sword
Alzheimer's disease is the most common form of dementia. Currently incurable, it increasingly impairs brain function over time, ultimately leading to death. The TAU researchers became interested in the disease while studying the brains of mice living in an "enriched environment" - an enlarged cage with running wheels, bedding and nesting material, a house, and frequently changing toys. Such environments have been shown to improve and maintain brain function in animals much as intellectual activity and physical fitness do in people.
The researchers ran a series of tests on a part of the mice's brains called the hippocampus, which plays a major role in memory and spatial navigation and is one of the earliest targets of Alzheimer's disease in humans. They found that, compared to mice in normal cages, the mice from the enriched environment developed higher levels of good proteins and lower levels of bad proteins. Then, for the first time, they identified the microRNAs responsible for regulating the expression of both good and bad proteins.
Armed with this new information, the researchers analyzed changes in the levels of microRNAs in the hippocampi of young, middle-aged, and old mice with an Alzheimer's-disease-like condition. They found that some of the microRNAs were expressed in exactly inverse amounts in mice with Alzheimer's disease as they were in mice from the enriched environment. The results were higher levels of bad proteins and lower levels of good proteins in the hippocampi of old mice with Alzheimer's disease. The microRNAs the researchers identified had already been shown or predicted to regulate the expression of proteins in ways that contributed to Alzheimer's disease. Their finding that the microRNAs are inversely regulated in mice from the enriched environment is important, because it suggests the molecules can be targeted by activities or drugs to preserve brain function.
Brain-busting potential
Two findings appear to have particular potential for treating people with Alzheimer's disease. In the brains of old mice with the disease, microRNA-325 was diminished, leading to higher levels of tomosyn, a protein that is well known to inhibit cellular communication in the brain. The researchers hope that eventually microRNA-325 can be used to create a drug to help Alzheimer's patients maintain low levels of tomosyn and preserve brain function. Additionally, the researchers found several important microRNAs at low levels starting in the brains of young mice. If the same can be found in humans, these microRNAs could be used as biomarker to detect Alzheimer's disease at a much earlier age than is now possible - at 30 years of age, for example, instead of 60.
"Our biggest hope is to be able to one day use microRNAs to detect Alzheimer's disease in people at a young age and begin a tailor-made
Now, Dr. Boaz Barak and a team of researchers in the lab of Prof. Uri Ashery of Tel Aviv University's Department of Neurobiology at the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience have identified a specific set of microRNAs that detrimentally regulate protein levels in the brains of mice with Alzheimer's disease and beneficially regulate protein levels in the brains of other mice living in a stimulating environment.
"We were able to create two lists of microRNAs - those that contribute to brain performance and those that detract - depending on their levels in the brain," says Dr. Barak. "By targeting these molecules, we hope to move closer toward earlier detection and better treatment of Alzheimer's disease."
Prof. Daniel Michaelson of TAU's Department of Neurobiology in the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience, Dr. Noam Shomron of TAU's Department of Cell and Developmental Biology and Sagol School of Neuroscience, Dr. Eitan Okun of Bar-Ilan University, and Dr. Mark Mattson of the National Institute on Aging collaborated on the study, published in Translational Psychiatry.
A double-edged sword
Alzheimer's disease is the most common form of dementia. Currently incurable, it increasingly impairs brain function over time, ultimately leading to death. The TAU researchers became interested in the disease while studying the brains of mice living in an "enriched environment" - an enlarged cage with running wheels, bedding and nesting material, a house, and frequently changing toys. Such environments have been shown to improve and maintain brain function in animals much as intellectual activity and physical fitness do in people.
The researchers ran a series of tests on a part of the mice's brains called the hippocampus, which plays a major role in memory and spatial navigation and is one of the earliest targets of Alzheimer's disease in humans. They found that, compared to mice in normal cages, the mice from the enriched environment developed higher levels of good proteins and lower levels of bad proteins. Then, for the first time, they identified the microRNAs responsible for regulating the expression of both good and bad proteins.
Armed with this new information, the researchers analyzed changes in the levels of microRNAs in the hippocampi of young, middle-aged, and old mice with an Alzheimer's-disease-like condition. They found that some of the microRNAs were expressed in exactly inverse amounts in mice with Alzheimer's disease as they were in mice from the enriched environment. The results were higher levels of bad proteins and lower levels of good proteins in the hippocampi of old mice with Alzheimer's disease. The microRNAs the researchers identified had already been shown or predicted to regulate the expression of proteins in ways that contributed to Alzheimer's disease. Their finding that the microRNAs are inversely regulated in mice from the enriched environment is important, because it suggests the molecules can be targeted by activities or drugs to preserve brain function.
Brain-busting potential
Two findings appear to have particular potential for treating people with Alzheimer's disease. In the brains of old mice with the disease, microRNA-325 was diminished, leading to higher levels of tomosyn, a protein that is well known to inhibit cellular communication in the brain. The researchers hope that eventually microRNA-325 can be used to create a drug to help Alzheimer's patients maintain low levels of tomosyn and preserve brain function. Additionally, the researchers found several important microRNAs at low levels starting in the brains of young mice. If the same can be found in humans, these microRNAs could be used as biomarker to detect Alzheimer's disease at a much earlier age than is now possible - at 30 years of age, for example, instead of 60.
"Our biggest hope is to be able to one day use microRNAs to detect Alzheimer's disease in people at a young age and begin a tailor-made
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