Posts tagged alzheimer's disease

High blood-sugar levels, such as those linked with Type 2 diabetes, make beta amyloid protein associated with Alzheimer’s disease dramatically more toxic to cells lining blood vessels in the brain, according to a new Tulane University study published in latest issue of the Journal of Alzheimer’s Disease.

The study supports growing evidence pointing to glucose levels and vascular damage as contributors to dementia.

“Previously, it was believed that Alzheimer’s disease was due to the accumulation of ‘tangles’ in neurons in the brain from overproduction and reduced removal of beta amyloid protein,” said senior investigator Dr. David Busija, regents professor and chair of pharmacology at Tulane University School of Medicine. “While neuronal involvement is a major factor in Alzheimer’s development, recent evidence indicates damaged cerebral blood vessels compromised by high blood sugar play a role. Even though the links among Type 2 diabetes, brain blood vessels and Alzheimer’s progression are unclear, hyperglycemia appears to play a role.”

Drs. Cristina Carvalho and Paula Moreira from the University of Coimbra in Portugal were co-investigators in the study.  

Researchers studied cell cultures taken from the lining of cerebral blood vessels, one from normal rats and another from mice with uncontrolled chronic diabetes. They exposed the cells to beta amyloid and different levels of glucose and later measured their viability. Cells exposed to high glucose or beta amyloid alone showed no changes in viability. However, when exposed to hyperglycemic conditions and beta amyloid, viability decreased by 40 percent. Researchers suspect the damage is due to oxidative stress from the mitochondria of the cell.

The cells from diabetic mice were more susceptible to damage and death to beta amyloid protein − even at normal glucose levels. The increased toxicity of beta amyloid may damage the blood-brain barrier, disrupt normal blood flow to the brain and decrease clearance of beta amyloid protein.

The study’s findings underscore the need to aggressively control blood sugar levels in diabetic individuals, Busija said.

(Source: tulane.edu)

TAU researchers identify specific molecules that could be targeted to treat the disorder

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 treatment based on our findings, right away," says Dr. Barak.

(Source: aftau.org)

If Alzheimer’s disease is to be treated in the future it requires an early diagnosis, which is not yet possible. Now researchers at higher education institutions such as Linköping University have identified six proteins in spinal fluid that can be used as markers for the illness.

Alzheimer’s causes great suffering and has a one hundred percent fatality rate. The breakdown of brain cells has been in progress for ten years or more by the time symptoms begin to appear. Currently there is no treatment that can stop the process.

(Image: Human neuroblastoma with cell nucleus in blue; beta amyloid as red aggregates within green-tinted lysosomes. Photo: Lotta Agholme.)

Most researchers now agree that one cause of the illness is toxic accumulations – plaques – of the beta amyloid protein. In a healthy brain, the cells are cleansed of such surplus products through lysosomes, the cells’ “waste disposal facilities” (green in the picture).

“In victims of Alzheimer’s, something happens to the lysosomes so that they can’t manage to take care of the surplus of beta amyloid. They fill up with junk that normally is broken down into its component parts and recycled,” says Katarina Kågedal, reader in Experimental Pathology at Linköping University. She led the study that is now being published in Neuromolecular Medicine.

The researchers’ hypothesis was that these changes in the brain’s lysosomal network could be reflected in the spinal fluid, which surrounds the brain’s various parts and drains down into the spinal column. They studied samples of spinal marrow from 20 Alzheimer’s patients and an equal number of healthy control subjects. The screening was aimed at 35 proteins that are associated with the lysosomal network.

“Six of these had clearly increased in the patients; none of them were previously known as markers for Alzheimer’s,” says Kågedal.

Her hope is that the group’s discovery will contribute to early diagnoses of the illness, which is necessary in the first stage in order to be able to begin reliable clinical tests of candidates for drugs. But perhaps the six lysosomal proteins could also be “drug targets” – targets for developing drugs.

“It may be a question of strengthening protection against plaque formation or reactivating the lysosomes so that they manage to break down the plaque,” Kågedal says.

The study was conducted on 20 anonymised, archived spinal marrow samples and the results were confirmed afterwards on an independent range of samples of equal size. All samples were provided by the Laboratory for Clinical Chemistry at Sahlgrenska University Hospital.

(Source: liu.se)

Buck Institute study provides insight for new therapeutics that target the interaction between ApoE4 and a Sirtuin protein

The major genetic risk factor for Alzheimer’s disease (AD), present in about two-thirds of people who develop the disease, is ApoE4, the cholesterol-carrying protein that about a quarter of us are born with. But one of the unsolved mysteries of AD is how ApoE4 causes the risk for the incurable, neurodegenerative disease. In research published this week in The Proceedings of the National Academy of Sciences, researchers at the Buck Institute found a link between ApoE4 and SirT1, an “anti-aging protein” that is targeted by resveratrol, present in red wine.

The Buck researchers found that ApoE4 causes a dramatic reduction in SirT1, which is one of seven human Sirtuins. Lead scientists Rammohan Rao, PhD, and Dale Bredesen, MD, founding CEO of the Buck Institute, say the reduction was found both in cultured neural cells and in brain samples from patients with ApoE4 and AD. “The biochemical mechanisms that link ApoE4 to Alzheimer’s disease have been something of a black box. However, recent work from a number of labs, including our own, has begun to open the box,” said Bredesen.

The Buck group also found that the abnormalities associated with ApoE4 and AD, such as the creation of phospho-tau and amyloid-beta, could be prevented by increasing SirT1. They have identified drug candidates that exert the same effect. “This research offers a new type of screen for Alzheimer’s prevention and treatment,” said Rammohan V. Rao, PhD, co-author of the study, and an Associate Research Professor at the Buck. “One of our goals is to identify a safe, non-toxic treatment that could be given to anyone who carries the ApoE4 gene to prevent the development of AD.”

In particular, the researchers discovered that the reduction in SirT1 was associated with a change in the way the amyloid precursor protein (APP) is processed. Rao said that ApoE4 favored the formation of the amyloid-beta peptide that is associated with the sticky plaques that are one of the hallmarks of the disease. He said with ApoE3 (which confers no increased risk of AD), there was a higher ratio of the anti-Alzheimer’s peptide, sAPP alpha, produced, in comparison to the pro-Alzheimer’s amyloid-beta peptide. This finding fits very well with the reduction in SirT1, since overexpressing SirT1 has previously been shown to increase ADAM10, the protease that cleaves APP to produce sAPP alpha and prevent amyloid-beta.

AD affects over 5 million Americans – there are no treatments that are known to cure, or even halt the progression of symptoms that include loss of memory and language. Preventive treatments are particularly needed for the 2.5% of the population that carry two genes for ApoE4, which puts them at an approximate 10-fold higher risk of developing AD, as well as for the 25% of the population with a single copy of the gene. The group hopes that the current work will identify simple, safe therapeutics that can be given to ApoE4 carriers to prevent the development of Alzheimer’s disease.

(Source: buckinstitute.org)

Poor sleep quality may impact Alzheimer’s disease onset and progression. This is according to a new study led by researchers at the Johns Hopkins Bloomberg School of Public Health who examined the association between sleep variables and a biomarker for Alzheimer’s disease in older adults. The researchers found that reports of shorter sleep duration and poorer sleep quality were associated with a greater β-Amyloid burden, a hallmark of the disease. The results are featured online in the October issue of JAMA Neurology.

“Our study found that among older adults, reports of shorter sleep duration and poorer sleep quality were associated with higher levels of β-Amyloid measured by PET scans of the brain,” said Adam Spira, PhD, lead author of the study and an assistant professor with the Bloomberg School’s Department of Mental Health. “These results could have significant public health implications as Alzheimer’s disease is the most common cause of dementia, and approximately half of older adults have insomnia symptoms.”

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. According to the National Institutes of Health, as many as 5.1 million Americans may have the disease, with first symptoms appearing after age 60. Previous studies have linked disturbed sleep to cognitive impairment in older people.

In a cross-sectional study of adults from the neuro-imagining sub-study of the Baltimore Longitudinal Study of Aging with an average age of 76, the researchers examined the association between self-reported sleep variables and β-Amyloid deposition. Study participants reported sleep that ranged from more than seven hours to no more than five hours. β-Amyloid deposition was measured by the Pittsburgh compound B tracer and PET (positron emission tomography) scans of the brain. Reports of shorter sleep duration and lower sleep quality were both associated with greater Αβ buildup.

“These findings are important in part because sleep disturbances can be treated in older people. To the degree that poor sleep promotes the development of Alzheimer’s disease, treatments for poor sleep or efforts to maintain healthy sleep patterns may help prevent or slow the progression of Alzheimer disease,” said Spira.  He added that the findings cannot demonstrate a causal link between poor sleep and Alzheimer’s disease, and that longitudinal studies with objective sleep measures are needed to further examine whether poor sleep contributes to or accelerates Alzheimer’s disease.

(Source: jhsph.edu)

NIH-funded study suggests sleep clears brain of molecules associated with neurodegeneration

A good night’s rest may literally clear the mind. Using mice, researchers showed for the first time that the space between brain cells may increase during sleep, allowing the brain to flush out toxins that build up during waking hours. These results suggest a new role for sleep in health and disease. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH.

“Sleep changes the cellular structure of the brain. It appears to be a completely different state,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center in New York, and a leader of the study.

For centuries, scientists and philosophers have wondered why people sleep and how it affects the brain. Only recently have scientists shown that sleep is important for storing memories. In this study, Dr. Nedergaard and her colleagues unexpectedly found that sleep may be also be the period when the brain cleanses itself of toxic molecules.

Their results, published in Science, show that during sleep a “plumbing” system, called the glymphatic system, may open, letting fluid flow rapidly through brain. Dr. Nedergaard’s lab recently discovered the glymphatic system helps control whether cerebrospinal fluid (CSF), a clear liquid surrounding the brain and spinal cord, flows through the brain.

“It’s as if Dr. Nedergaard and her colleagues have uncovered a network of hidden caves and  these exciting results highlight the potential importance of the network in normal brain function,” said Roderick Corriveau, Ph.D., a program director at NINDS.

Initially the researchers studied the system by injecting dye into the CSF of mice and watching it flow through their brains while simultaneously monitoring electrical brain activity. The dye flowed rapidly when the mice were unconscious, either asleep or anesthetized.  In contrast, the dye barely flowed when the same mice were awake.

“We were surprised by how little flow there was into the brain when the mice were awake,” said Dr. Nedergaard. “It suggested that the space between brain cells changed greatly between conscious and unconscious states.”

To test this idea, the researchers inserted electrodes into the brain to directly measure the space between brain cells. They found that the space inside the brains increased by 60 percent when the mice were asleep or anesthetized. 

“These are some dramatic changes in extracellular space,” said Charles Nicholson, Ph.D., a professor at New York University’s Langone Medical Center and an expert in measuring the dynamics of brain fluid flow and how it influences nerve cell communication.

Certain brain cells, called glia, control flow through the glymphatic system by shrinking or swelling. Noradrenaline is an arousing hormone that is also known to control cell volume. Treating awake mice with drugs that block noradrenaline induced sleep and increased brain fluid flow and the space between cells, further supporting the link between the glymphatic system and sleep.

Previous studies suggest that toxic molecules involved in neurodegenerative disorders accumulate in the space between brain cells. In this study, the researchers tested whether the glymphatic system controls this by injecting mice with radiolabeled beta-amyloid, a protein associated with Alzheimer’s disease, and measuring how long it lasted in their brains when they were asleep or awake. Beta-amyloid disappeared faster in mice brains when the mice were asleep, suggesting sleep normally clears toxic molecules from the brain.

“These results may have broad implications for multiple neurological disorders,” said Jim Koenig, Ph.D., a program director at NINDS. “This means the cells regulating the glymphatic system may be new targets for treating a range of disorders.”

The results may also highlight the importance of sleep.

“We need sleep.  It cleans up the brain,” said Dr. Nedergaard.

(Source: ninds.nih.gov)

Johns Hopkins scientists have developed new drugs that — at least in a laboratory dish — appear to halt the brain-destroying impact of a genetic mutation at work in some forms of two incurable diseases, amyotrophic lateral sclerosis (ALS) and dementia.

They made the finding by using neurons they created from stem cells known as induced pluripotent stem cells (iPS cells), which are derived from the skin of people with ALS who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.

“Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials,” says Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the research described online in the journal Neuron. “But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It’s individualized brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology.”

Scientists in 2011 discovered that more than 40 percent of patients with an inherited form of ALS and at least 10 percent of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene. The mutation also occurs very often in people with frontotemporal dementia, the second-most-common form of dementia after Alzheimer’s disease. The same research appeared to explain why some people develop both ALS and the dementia simultaneously and that, in some families, one sibling might develop ALS while another might develop dementia.

In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times. Rothstein, who is also director of the Johns Hopkins Brain Science Institute and the Robert Packard Center for ALS Research, used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the “repeats” were causing the brain cell death characteristic of ALS.

In a series of experiments, Rothstein says, they discovered that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted. Normally, RNA-binding proteins facilitate the production of RNA. Instead, in the iPS neurons with the C9ORF72 mutation, the RNA made from the repeating GGGGCC strings was bunching up, gumming up the works by acting like flypaper and grabbing hold of the extremely important RNA binding proteins, including one known as ADARB2,  needed for the proper production of many other cellular RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.

To counter this effect, the researchers developed a number of chemical compounds targeting the problem. This compound behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.

Rothstein says Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing it in human ALS patients with the C9ORF72 mutation in the next several years. In collaboration with the National Institutes of Health, plans are already underway to begin to identify a group of patients with the C9ORF72 mutation for future research.

Rita Sattler, Ph.D., an assistant professor of neurology at Johns Hopkins and the co-investigator of the study, says without iPS technology, the team would have had a difficult time studying the C9ORF72 mutation. “Typically, researchers engineer rodents with mutations that mimic the human glitches they are trying to research and then study them,” she says. “But the nature of the multiple repeats made that nearly impossible.” The iPS cells did the job just as well or even better than an animal model, Sattler says, in part because the experiments could be done using human cells.

“An iPS cell line can be used effectively and rapidly to understand disease mechanisms and as a tool for therapy development,” Rothstein adds. “Now we need to see if our findings translate into a valuable treatment for humans.”

The researchers also analyzed brain tissue from people with the C9ORF72 mutation who died of ALS. They saw evidence of this bunching up and found that the many genes that were altered as a consequence of this mutation in the iPS cells were also abnormal in the brain tissue, thereby showing that iPS cells can be a faithful tool to study the human disease and discover effective therapies.

In the future, the scientists will look at cerebral spinal fluid from ALS patients with the C9ORF72 mutation, searching for proteins that were found both in the fluid and the iPS cells. These may pave the way to develop markers that can be studied by clinicians to see if the treatment is working once the drug therapy is moved to clinical trials.

ALS, sometimes known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, destroys nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary. There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival, Rothstein notes.

(Source: hopkinsmedicine.org)