Tag: Alzheimer's disease

Categories : Neurodegenerative DiseasesTags : 2 Comments

Light Therapy may Relieve Alzheimer’s Circadian Disruption

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New Alzheimer’s research suggests that enhanced light sensitivity may contribute to ‘sundowning’, which is the worsening of symptoms late in the day, thereby spurring sleep disruptions thought to contribute to the disease’s progression.

Published in Frontiers in Aging Neuroscience, these new insights from UVA Health into the disruptions of the biological clock seen in Alzheimer’s could lead to new treatments and symptom management, the researchers say. For example, caregivers often struggle with the erratic sleep patterns caused by Alzheimer’s patients’ altered circadian rhythms. Light therapy, the new research suggests, might be an effective tool to help manage that.

Better understanding Alzheimer’s effects on circadian rhythms could have implications for prevention. Poor sleep quality in adulthood is a risk factor for Alzheimer’s, as brains at rest naturally cleanse themselves of amyloid beta proteins that are thought to form harmful tangles in Alzheimer’s.

“Circadian disruptions have been recognised in Alzheimer’s disease for a long time, but we’ve never had a very good understanding of what causes them,” said researcher Thaddeus Weigel, a graduate student working with Heather Ferris, MD, PhD. “This research points to changes in light sensitivity as a new, interesting possible explanation for some of those circadian symptoms.”

Alzheimer’s hallmark is progressive memory loss, to the point that patients can forget their own loved ones, but there can be many other symptoms, such as restlessness, aggression, poor judgment and endless searching. These symptoms often worsen in the evening and at night.

Ferris and her collaborators used a mouse model of Alzheimer’s to better understand what happens to the biological clock in Alzheimer’s disease. They essentially gave the mice “jet lag” by altering their exposure to light, then examined how it affected their behaviour. The Alzheimer’s mice reacted very differently to control mice.

The Alzheimer’s mice, the scientists found, adapted to a six-hour time change significantly more quickly than the control mice. This, the scientists suspect, is the result of a heightened sensitivity to changes in light. While our biological clocks normally take cues from light, this adjustment happens gradually – thus, jet lag when we travel great distances. Our bodies need time to adapt. But for the Alzheimer’s mice, this change happened abnormally fast.

The researchers initially thought this might be because of neuroinflammation. So they looked at immune cells called microglia that have become promising targets in developing better Alzheimer’s treatments. But the scientists ultimately ruled out this hypothesis, determining that microglia did not make a difference in how quickly mice adapted. (Though targeting microglia might be beneficial for other reasons.)

Notably, the UVA scientists also ruled out another potential culprit: “mutant tau,” an abnormal protein that forms tangles in the Alzheimer’s brain. The presence of these tangles also did not make a difference in how the mice adapted.

The researchers’ results ultimately suggest there is an important role for the retina in the enhanced light sensitivity in Alzheimer’s, and that gives researchers a promising avenue to pursue as they work to develop new ways to treat, manage and prevent the disease.

“These data suggest that controlling the kind of light and the timing of the light could be key to reducing circadian disruptions in Alzheimer’s disease,” Ferris said. “We hope that this research will help us to develop light therapies that people can use to reduce the progression of Alzheimer’s disease.”

Source: University of Virginia Health System

Categories : Exercise Neurodegenerative DiseasesTags :

Could an Alzheimer’s Treatment be Lurking in a Bodybuilder’s Supplement?

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A safe treatment against Alzheimer’s progression may be hidden in a common bodybuilding supplement. Researchers recently discovered that a muscle-building supplement called beta-hydroxy beta-methylbutyrate (HMB), may help protect memory, reduce plaques and ultimately help prevent the progression of Alzheimer’s disease. The researchers published their results in the journal Cell Reports.

HMB is a safe over-the-counter supplement, which bodybuilders regularly use to enhance exercise-related muscle strength and growth.

“This may be one of the safest and the easiest approaches to halt disease progression and protect memory in Alzheimer’s disease patients,” said Kalipada Pahan, PhD, at RUSH Medical College.

Studies in mouse models of Alzheimer’s have shown that HMB successfully reduces plaques and increases factors for neuronal growth to protect learning and memory, according to neurological researchers at RUSH.

“Understanding how the disease works is important to developing effective drugs to protect the brain and stop the progression of Alzheimer’s disease,” Pahan said.

Previous studies indicate that a family of proteins known as neurotrophic factors are drastically decreased in the brains of people with Alzheimer’s disease and have been found to help in survival and function of neurons, which are cells that receive and send messages from the body to the brain and vice versa.

“Our study found that after oral consumption, HMB enters into the brain to increase these beneficial proteins, restore neuronal connections and improve memory and learning in mice with Alzheimer’s-like pathology, such as plaques and tangles,” Pahan said.

The study findings indicate that HMB stimulates the nuclear hormone receptor PPARα within the brain that regulates the transport of fatty acids, which is key to the success of HMB as a neuroprotective supplement.

“If mouse results with HMB are replicated in Alzheimer’s disease patients, it would open up a promising avenue of treatment of this devastating neurodegenerative disease,” Pahan said.

Source: Rush University Medical Center

Categories : Neurodegenerative Diseases New Compounds and TreatmentsTags :

Third Alzheimer’s Drug is ‘Opening a Chapter in a New Era’

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With yet a third new Alzheimer’s drug, the monoclonal antibody donanemab, expected to be approved by the Food and Drug Administration (FDA), the field is beginning to show progress in the fight to slow the disease. But the drugs work best for those in the earliest stages of Alzheimer’s, and other therapies will be needed to help those with advanced disease, according to Gil Rabinovici, MD, director of the UCSF Alzheimer’s Disease Research Center.

This is likely “just the opening chapter in a new era of molecular therapies for Alzheimer’s disease and related neurodegenerative disorders,” Rabinovici wrote in an editorial that is being published along with the results of the latest drug, donanemab, in JAMA. Rabinovici was not involved in the trial.

Donanemab is a monoclonal antibody, like the two earlier Alzheimer’s drugs, aducanumab (Aduhelm) and lecanemab (Leqembi). These drugs attack plaques in the brain that are made of a protein called amyloid. They disrupt cell function and lead to the rapid spread of another protein called tau. Both amyloid and tau contribute to the development of Alzheimer’s disease.

The trial showed donanemab slowed cognitive decline by 35% compared with placebo in patients with low-to-intermediate levels of tau in the brain. These results are similar to those reported with Leqembi, which received FDA approval earlier this month. In the donanemab trial, patients also experienced a 40% lower risk of progressing from mild cognitive impairment to mild dementia, or from mild-to-moderate dementia.

Donanemab was better at removing amyloid plaques compared to Aduhelm and Leqembi. It reduced tau concentrations in the blood, but not in a key area of the brain.

While these results are encouraging, Rabinovici said an in-depth analysis still is needed to understand how these findings affect patient outcomes.

Limited benefit in advanced disease

Patients with more advanced disease showed little to no benefit compared to those who received the placebo. Together with the drug’s potentially serious side effects, this should push experts to “aim higher in developing more impactful and safer treatments,” wrote Rabinovici, who is affiliated with the UCSF Memory and Aging Center, departments of Neurology, Radiology and Biomedical Imaging, as well as the Weill Institute for Neurosciences.

Donanemab should be restricted to patients with low-to-intermediate levels of tau, which indicates mild disease. Other trials are evaluating how well monoclonal antibodies work in the earliest phase of the disease before symptoms appear.

Like the two other new Alzheimer’s drugs, donanemab was associated with ARIA, amyloid-related imaging abnormalities that may include brain swelling and microbleeds. Serious ARIA occurred in 3.7% of patients, including three deaths. Risks were higher among patients with the APOE4 gene, which is related to an increased risk for Alzheimer’s. For that reason, Rabinovici said, genetic testing should be recommended prior to monoclonal antibody treatment.

While ARIA has generally been managed safely in clinical trials, Rabinovici urged caution as these drugs enter into real-world practice. He suggested limiting access to patients with normal pre-treatment MRIs, repeating MRIs at regular intervals and stopping or suspending treatment when ARIA occurs.

Lack of racial and ethnic diversity was a major limitation of the trial. Just 8.6% of the 1,251 U. S. participants were non-white. Rabinovici said this raises ethical concerns about the “generalisability of results to populations at highest risk,” noting studies that have shown higher rates of dementia in Black and Latino populations.

Given the anticipated high cost of donanemab and high patient demand, Rabinovici said it might make sense to limit the treatment duration to the time needed to clear amyloid plaques from the brain, which is the approach pioneered in the trial. He said this could “greatly enhance the feasibility of treatment for patients, clinicians, insurers and health systems.”

Source: University of California – San Francisco

Note: this article previously used an incorrectly attributed image. This has since been taken down and replaced.

Categories : Neurodegenerative Diseases Pain ManagementTags :

Alzheimer’s Patients have an Altered Perception of Pain

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New research published in Nature Communications has found that in a mouse model mimicking Alzheimer’s Disease (AD) pain signals are not processed in the same way as in healthy mice. The research, from King’s College London, suggests that the perception of pain in people with Alzheimer’s Disease may be altered, and asks whether changes in management of pain in people with AD could improve their quality of life.

While chronic musculoskeletal pain is common in individuals with AD, it remains largely untreated as it can go unreported due to the cognitive deficits attached to the disease.

In this study, the researchers sought to explore whether there is also an alteration in the body’s response to pain by the nervous system in people with AD.

In healthy mice, pain signals are transmitted from the point of origin to the central nervous system to initiate an immune response. The protein Galectin-3 has been demonstrated to be responsible for pain signal transmission to the spinal cord. Upon reaching the spinal cord, it binds to another protein, TLR4, to initiate the immune response.

In this study, researchers used an AD mice model and gave them rheumatoid arthritis, a type of chronic inflammatory disease, through blood transfer. They observed an increase in allodynia, pain caused by a stimulus that doesn’t normally provoke pain, as a response to the inflammation. They also saw increased activation of a microglia in the spinal cord. They determined that these effects were regulated by TLR4.

Researchers found that the mice with AD lacked TLR4 in the immune cells of their central nervous system and were therefore unable to respond to pain in the typical way as the signals were not being perceived.

This resulted in the mice with AD developing less joint inflammation related pain, and a less powerful immune cell response to the pain signals received by the central nervous system.

Professor Marzia Malcangio, Professor of Neuropharmacology at King’s IoPPN and the study’s senior author said, “Nociceptive pain – pain which is the result of tissue damage – is the second most prevalent comorbidity in individuals with Alzheimer’s disease. Our study has shown that, in mice with Alzheimer’s, the body’s ability to process that pain is altered due to the lack of TLR4; a protein vital to the immune response process in the central nervous system.

“These are important findings, as untreated pain can contribute to the psychiatric symptoms of the disease. Increasing our understanding of this area could, with more research, lead to more effective treatments and ultimately improve people’s quality of life.”

George Sideris-Lampretsas, a PhD student at King’s IoPPN and the study’s first author said, “The results of this study have the potential to make an impact, not only by identifying Galectin-3/TLR4 as a potential therapeutic target for chronic pain, but most importantly by raising awareness around the underreported and untreated pain experienced by patients with AD.”

Source: King’s College London

Categories : Neurodegenerative Diseases VaccinesTags :

Could the BCG Vaccine Reduce Alzheimer’s Risk?

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The Bacillus Calmette-Guérin (BCG) for tuberculosis vaccine has a number additional beneficial effects, and is currently a recommended therapy for non–muscle-invasive bladder cancer. In a new study published in JAMA Network Open, treatment with the BCG vaccine was associated with a reduced risk of Alzheimer’s disease and related dementias.

Although previous research has suggested a link between the BCG vaccine and a lower risk of dementia, studies were limited by size, study design, or analytical methods. To conduct a more robust study, researchers followed 6467 individuals for up to 15 years after they were diagnosed with non–muscle-invasive bladder cancer.

The group included 3388 patients who underwent BCG vaccine treatment and 3079 who served as controls, matched by factors such as age, sex, and medical co-morbidities.

During follow-up, 202 patients in the BCG vaccine group and 262 in the control group developed Alzheimer’s disease and related dementias. The incidence was 8.8 per 1000 person-years and 12.1 per 1000 person-years in the respective groups.

Analyses revealed that treatment with the BCG vaccine was associated with a 20% lower risk of Alzheimer’s disease and related dementias. The protective association was greater in patients aged 70 years or older. Additionally, during follow-up, 751 patients in the BCG vaccine group and 973 in the control group died. Thus, treatment with BCG vaccine was associated with a 25% lower risk of death.

Study leader Marc Weinberg, MD, Ph.D., an Instructor in Psychiatry at MGH, said: “A vaccine like BCG, if proven effective, is a perfect example of a cost-effective, population-health–based solution to a devastating illness like Alzheimer’s disease. We are shifting our focus towards studying the potential benefits of BCG vaccination of older adults in Alzheimer’s disease–related clinical trials.”

If a causal link is found, it will be important to understand the mechanisms involved. Weinberg and his colleagues note that the BCG vaccine’s effects on the immune system may play a role.

Source: Massachusetts General Hospital

Categories : Gender Neurodegenerative DiseasesTags :

Sex Differences in Alzheimer’s Rates may be Caused by Stress Responses

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Women are about twice as likely as men to be diagnosed with Alzheimer’s disease. Some of that is age: women outlive men in most countries, and advanced age is the strongest risk factor for Alzheimer’s. But not all of it explains the excess risk.

One such factor may be stress may be one such reason. A study published in Brain shows that the effect stress has on the brain differs by sex, at least in mice. In stressful situations, levels of the Alzheimer’s protein amyloid beta rises sharply in the brains of females but not males. In addition, the researchers identified a molecular pathway that is active in brain cells from female mice but not male mice, and showed that it accounts for the divergent responses to stress.

The findings, from researchers at Washington University School of Medicine in St. Louis, add to a growing collection of evidence that sex matters in health and disease. From cancer to heart disease to arthritis, scientists have found differences between males and females that could potentially affect how men and women respond to efforts to prevent or treat chronic diseases.

“How women respond to stress versus how men respond to stress is an important area of research that has implications for not just Alzheimer’s disease but other conditions, too,” said co-corresponding author Carla M. Yuede, PhD, an associate professor of psychiatry. “In recent years, the National Institutes of Health (NIH) has prioritized understanding sex differences in medicine. Stress is one area in which you can clearly see a difference between males and females. This study shows that reducing stress may be more beneficial for women than men, in terms of lowering the risk of Alzheimer’s disease.”

Stress falls into the category of socioeconomic risk factors, along with factors such as depression and social isolation, that together account for an estimated 8% of the risk of developing Alzheimer’s. That risk calculation, however, doesn’t take sex into account. Women consistently report higher levels of stress than men, and it affects them differently.

Corresponding author John Cirrito, PhD, an associate professor of neurology; Yuede; and first author Hannah Edwards, a graduate student in Cirrito’s lab, reasoned that stress also may affect women’s brains differently than men’s, and these differences may help explain the sex imbalance in Alzheimer’s disease.

To find out, they measured levels of amyloid beta in the brains of mice every hour for 22 hours, beginning eight hours before the mice experienced stress. The experience was equally stressful for male and female mice, as measured by the levels of stress hormones in their blood. But the responses in their brains were not the same.

In female mice, amyloid beta levels rose significantly within the first two hours and stayed elevated through the end of the monitoring period. In male mice, brain amyloid levels did not change overall, although about 20% of them did show a delayed and weak rise in amyloid levels.

Further experiments revealed that the difference comes down to a cellular stress response pathway in brain cells. Stress causes the release of a hormone known as corticotropin releasing factor. Neurons from female rodents take up the stress hormone, triggering a cascade of events that results in increasing levels of amyloid beta in the brain. In contrast, neurons from male rodents lack the ability to take up the stress hormone. It is not known whether there are similar sex differences in how human neurons take up stress hormones.

“There’s a fundamental biological difference between males and females in how they respond to stress at the cellular level, in both mice and people,” Cirrito said. “We don’t think that stress is the sole factor driving the sex difference in Alzheimer’s disease. There are many other differences between men and women – in hormones, lifestyle, other diseases they have – that undoubtedly contribute in some way. But that stress is driving one aspect of this sex difference I think is very likely.”

Source: Washington University School of Medicine

Categories : Neurodegenerative DiseasesTags :

Gene Silencing Treatment Lowers Tau Proteins in Alzheimer’s Patients

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Neurons in the brain of an Alzheimer’s patient, with amyloid plaques caused by tau proteins. Credit: NIH

In a preliminary trial, a new ‘gene silencing’ treatment has been able to safely and successfully lower levels of the harmful tau protein known to cause the disease. This success, published in Nature Medicine, demonstrates that a ‘gene silencing’ approach could work in dementia and Alzheimer’s disease.

The approach uses a drug called BIIB080 (/IONIS-MAPTRx), which is an antisense oligonucleaotide (used to stop RNA producing a protein), to ‘silence’ the gene coding for the tau protein – known as the microtubule-associated protein tau (MAPT) gene. This prevents the gene from being translated into the protein in a doseable and reversible way. It also reduces production of that protein, altering the course of disease.

Further trials will be needed in larger groups of patients to determine whether this leads to clinical benefit, but the phase 1 results are the first indication that this method has a biological effect.

There are currently no treatments targeting tau. The drugs aducanumab and lecanemab – recently approved for use in some situations by the FDA – target a separate disease mechanism in AD, the accumulation of amyloid plaques.

The phase 1 trial enrolled 46 patients with an average age of 66, and looked at the safety of BIIB080, what it does in the body, and how well it targets the MAPT gene. The trial compared three doses of the drug, given by intrathecal injection (an injection into the nervous system via the spinal canal), with the placebo.

Results show that the drug was well tolerated, with all patients completing the treatment period and over 90% completing the post-treatment period.

Patients in both the treatment and placebo groups experienced either mild or moderate side effects – the most common being a headache after injection of the drug. However, no serious adverse events were seen in patients given the drug.

The research team also looked at two forms of the tau protein in the central nervous system (CNS) – a reliable indicator of disease – over the duration of the study.

They found a greater than 50% reduction in levels of total tau and phosphor tau concentration in the CNS after 24 weeks in the two treatment groups that received the highest dose of the drug.

Consultant neurologist Dr Catherine Mummery, who led the study, said: “We will need further research to understand the extent to which the drug can slow progression of physical symptoms of disease and evaluate the drug in older and larger groups of people and in more diverse populations.

“But the results are a significant step forward in demonstrating that we can successfully target tau with a gene silencing drug to slow – or possibly even reverse – Alzheimer’s disease, and other diseases caused by tau accumulation in the future.”

Source: Imperial College London

Categories : Neurodegenerative DiseasesTags :

A Sleeping Pill Lowers Alzheimer’s Protein Levels

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An early sign of Alzheimer’s disease is sleep disturbance – many people eventually diagnosed with Alzheimer’s start experiencing difficulty falling and staying asleep years before the emergence of cognitive problems such as memory loss and confusion. In a vicious circle, Alzheimer’s disease disrupts sleep, and poor sleep accelerates harmful changes to the brain.

Now, researchers at Washington University School of Medicine in St. Louis have identified a possible way to help break that cycle. Published in Annals of Neurology, a small, two-night study has shown that people who took a sleeping pill before bed experienced a drop in the levels of key Alzheimer’s proteins – a good sign, since higher levels of such proteins tracks with worsening disease. The study, which involved a sleeping aid known as suvorexant that is already approved by the Food and Drug Administration (FDA) for insomnia, hints at the potential of sleep medications to slow or stop the progression of Alzheimer’s disease, although much more work is needed to confirm the viability of such an approach.

“This is a small, proof-of-concept study. It would be premature for people who are worried about developing Alzheimer’s to interpret it as a reason to start taking suvorexant every night,” said senior author Brendan Lucey, MD, an associate professor of neurology and director of Washington University’s Sleep Medicine Center. “We don’t yet know whether long-term use is effective in staving off cognitive decline, and if it is, at what dose and for whom. Still, these results are very encouraging. This drug is already available and proven safe, and now we have evidence that it affects the levels of proteins that are critical for driving Alzheimer’s disease.”

Suvorexant belongs to a class of insomnia medications known as dual orexin receptor antagonists. Orexin is a natural biomolecule that promotes wakefulness. When orexin is blocked, people fall asleep. Three orexin inhibitors have been approved by the FDA, and more are in the pipeline.

Alzheimer’s disease begins when plaques of the protein amyloid beta start building up in the brain. After years of amyloid accumulation, a second brain protein, tau, begins to form tangles that are toxic to neurons. People with Alzheimer’s disease start experiencing cognitive symptoms such as memory loss around the time tau tangles become detectable.

Lucey and colleagues were among the first to show in people that poor sleep is linked to higher levels of both amyloid and tau in the brain. The question remains as to whether good sleep has the opposite effect – a reduction in amyloid and tau levels, and a halt in or reversal of the progress of Alzheimer’s disease – but mouse studies with orexin inhibitors have been promising.

As a first step to assess the effect of orexin inhibitors on people, Lucey and colleagues recruited 38 participants ages 45 to 65 and with no cognitive impairments to undergo a two-night sleep study. The participants were given a lower dose (10 mg) of suvorexant (13 people), a higher dose (20 mg) of suvorexant (12 people) or a placebo (13 people) at 9 p.m. and then went to sleep in a clinical research unit at Washington University. Researchers withdrew a small amount of cerebrospinal fluid via spinal tap every two hours for 36 hours, starting one hour before the sleeping aid or placebo was administered, to measure how amyloid and tau levels changed over the next day and a half.

Amyloid levels dropped 10% to 20% in the cerebrospinal fluid of people who had received the high dose of suvorexant compared to people who had received placebo, and the levels of a key form of tau known as hyperphosphorylated tau dropped 10% to 15%, compared to people who had received placebo. Both differences are statistically significant. There was not a significant difference between the people who received a low dose of suvorexant and those who received the placebo.

By 24 hours after the first dose, hyperphosphorylated tau levels in the high-dose group had risen, while amyloid levels remained low compared to the placebo group. A second dose of suvorexant, administered on the second night, sent the levels of both proteins down again for people in the high-dose group.

“If we can lower amyloid every day, we think the accumulation of amyloid plaques in the brain will decrease over time,” Lucey said. “And hyperphosphorylated tau is very important in the development of Alzheimer’s disease, because it’s associated with forming tau tangles that kill neurons. If you can reduce tau phosphorylation, potentially there would be less tangle formation and less neuronal death.”

The study is preliminary, since it only looked at the effect of two doses of the drug in a small group of participants. Lucey has studies underway to assess the longer-term effects of orexin inhibitors in people at higher risk of dementia.

“Future studies need to have people taking these drugs for months, at least, and measuring the effect on amyloid and tau over time,” Lucey said. “We’re also going to be studying participants who are older and may still be cognitively healthy, but who already have some amyloid plaques in their brains. This study involved healthy middle-aged participants; the results may be different in an older population.

“I’m hopeful that we will eventually develop drugs that take advantage of the link between sleep and Alzheimer’s to prevent cognitive decline,” he continued. “We’re not quite there yet. At this point, the best advice I can give is to get a good night’s sleep if you can, and if you can’t, to see a sleep specialist and get your sleep problems treated.”

Source: Washington University School of Medicine

Categories : Neurodegenerative DiseasesTags :

A Genetic Treatment for ALS That Restores Key Protein May Be Possible

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DNA repair
Source: Pixabay/CC0

In virtually all persons with amyotrophic lateral sclerosis (ALS) and in up to half of all cases of Alzheimer’s disease (AD) and frontotemporal dementia, a protein called TDP-43 is lost from its normal location in the nucleus of the cell. In turn, this triggers the loss of stathmin-2, a protein crucial to regeneration of neurons and the maintenance of their connections to muscle fibres.

Writing in Science, a team of scientists demonstrate that stathmin-2 loss can be rescued using designer DNA drugs that restore normal processing of protein-encoding RNA.

“With mouse models we engineered to misprocess their stathmin-2 encoding RNAs, like in these human diseases, we show that administration of one of these designer DNA drugs into the fluid that surrounds the brain and spinal cord restores normal stathmin-2 levels throughout the nervous system,” said senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at University of California San Diego School of Medicine.

Cleveland is broadly credited with developing the concept of designer DNA drugs, which act to either turn on or turn off genes associated with many degenerative diseases of the aging human nervous system, including ALS, AD, Huntington’s disease and cancer.

Several designer DNA drugs are currently in clinical trials for multiple diseases. One such drug has been approved to treat a childhood neurodegenerative disease called spinal muscular atrophy.

The new study builds upon ongoing research by Cleveland and others regarding the role and loss of TDP-43, a protein associated with ALS, AD and other neurodegenerative disorders. In ALS, TDP-43 loss impacts the motor neurons that innervate and trigger contraction of skeletal muscles, causing them to degenerate, eventually resulting in paralysis.

“In almost all of instances of ALS, there is aggregation of TDP-43, a protein that functions in maturation of the RNA intermediates that encode many proteins. Reduced TDP-43 activity causes misassembly of the RNA-encoding stathmin-2, a protein required for maintenance of the connection of motor neurons to muscle,” said Cleveland.

“Without stathmin-2, motor neurons disconnect from muscle, driving paralysis that is characteristic of ALS. What we have now found is that we can mimic TDP-43 function with a designer DNA drug, thereby restoring correct stathmin-2 RNA and protein level in the mammalian nervous system.”

Specifically, the researchers edited genes in mice to contain human STMN2 gene sequences and then injected antisense oligonucleotides – small DNA or RNA pieces that can bind to specific RNA molecules, blocking their ability to make a protein or changing how their final RNAs are assembled – into cerebral spinal fluid. The injections corrected STMN2 pre-mRNA misprocessing and restored stathmin-2 protein expression fully independent of TDP-43 function.

“Our findings lay the foundation for a clinical trial to delay paralysis in ALS by maintaining stathmin-2 protein levels in patients using our designer DNA drug,” Cleveland said.

Source: University of California – San Diego

Categories : Diet and Nutrition Neurodegenerative DiseasesTags :

Fructose Could Drive Alzheimer’s Disease

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An ancient human instinct for foraging, fuelled by fructose production in the brain, may hold clues to the development and possible treatment of Alzheimer’s disease (AD), according to a new study published recently in The American Journal of Clinical Nutrition.

The findings provide a new way of looking at the neurodegenerative disease.

“We make the case that Alzheimer’s disease is driven by diet,” said the study’s lead author Richard Johnson, MD, professor at the University of Colorado School of Medicine specializing in renal disease and hypertension. The study co-authors include Maria Nagel, MD, research professor of neurology at the CU School of Medicine.

Johnson and his team suggest that AD is a harmful adaptation of an evolutionary survival pathway used in animals and our distant ancestors during times of scarcity.

“A basic tenet of life is to assure enough food, water and oxygen for survival,” the study said. “Much attention has focused on the acute survival responses to hypoxia and starvation. However, nature has developed a clever way to protect animals before the crisis actually occurs.”

When threatened with the possibility of starvation, early humans developed a survival response which sent them foraging for food. Yet foraging is only effective if metabolism is inhibited in various parts of the brain. Foraging requires focus, rapid assessment, impulsivity, exploratory behavior and risk taking. It is enhanced by blocking whatever gets in the way, like recent memories and attention to time. Fructose, a kind of sugar, helps damp down these centers, allowing more focus on food gathering.

In fact, the researchers found the entire foraging response was set in motion by the metabolism of fructose whether it was eaten or produced in the body. Metabolizing fructose and its byproduct, intracellular uric acid, was critical to the survival of both humans and animals.

The researchers noted that fructose reduces blood flow to the brain’s cerebral cortex involved in self-control, as well as the hippocampus and thalamus. Meanwhile, blood flow increased around the visual cortex associated with food reward. All of this stimulated the foraging response.

“We believe that initially the fructose-dependent reduction in cerebral metabolism in these regions was reversible and meant to be beneficial,” Johnson said. “But chronic and persistent reduction in cerebral metabolism driven by recurrent fructose metabolism leads to progressive brain atrophy and neuron loss with all of the features of AD.”

Johnson suspects the survival response, what he calls the `survival switch,’ that helped ancient humans get through periods of scarcity, is now stuck in the `on’ position in a time of relative abundance. This leads to the overeating of high fat, sugary and salty food prompting excess fructose production.

Fructose produced in the brain can lead to inflammation and ultimately Alzheimer’s disease, the researchers theorised. Animals given fructose show memory lapses, a loss in the ability to navigate a maze and inflammation of the neurons.

“A study found that if you keep laboratory rats on fructose long enough they get tau and amyloid beta proteins in the brain, the same proteins seen in Alzheimer’s disease,” Johnson said. “You can find high fructose levels in the brains of people with Alzheimer’s as well.”

Johnson suspects that the tendency of some AD patients to wander off might be a vestige of the ancient foraging response.

The study said more research is needed on the role of fructose and uric acid metabolism in AD.

“We suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine if there is potential benefit in the prevention, management or treatment of this disease,” Johnson said.

Source: University of Colorado Anschutz Medical Campus