Tag: Alzheimer's disease

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New Immune Solution Suggests Taking the STING out of Alzheimer’s

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A new way of thinking about Alzheimer’s disease has yielded a discovery that could be the key to stopping the cognitive decline seen in Alzheimer’s and other neurodegenerative diseases.

University of Virginia School of Medicine scientists have been investigating the possibility that Alzheimer’s is caused, at least in part, by the immune system’s wayward attempts to fix DNA damage in the brain. Their research reveals that an immune molecule called STING drives the formation of the harmful plaques and protein tangles thought responsible for Alzheimer’s. Blocking the molecule protected lab mice from mental decline, the researchers say.

An important player in the brain’s immune system, STING also may be a key contributor to Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), dementia and other memory-robbing conditions. That means that developing treatments to control its activity could have far-reaching benefits for many patients facing now-devastating diagnoses.

“Our findings demonstrate that the DNA damage that naturally accumulates during aging triggers STING-mediated brain inflammation and neuronal damage in Alzheimer’s disease,” said researcher John Lukens, PhD, director of UVA’s Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases. “These results help to explain why aging is associated with increased Alzheimer’s risk and uncover a novel pathway to target in the treatment of neurodegenerative diseases.”

Alarming Trends in Alzheimer’s

Alzheimer’s is a growing problem, with researchers working frantically to find ways to better understand and treat the condition.

The causes of Alzheimer’s remain murky, but scientists are increasingly coming to appreciate the role of the immune system in the disease’s development. STING is part of that immune response; the molecule helps direct the clearance of viruses and stressed cells harboring DNA damage.

While STING is an important defender of the brain, it can also become hyperactive and cause harmful inflammation and tissue damage. That had Lukens and his team eager to determine what part it could be playing in Alzheimer’s. Blocking the molecule’s activity in lab mice, they found, helped prevent Alzheimer’s plaque formation, altered the activity of immune cells called microglia and redirected the workings of important genes, among other effects.

“We found that removing STING dampened microglial activation around amyloid plaques, protected nearby neurons from damage and improved memory function in Alzheimer’s model mice,” said researcher Jessica Thanos, part of UVA’s Department of Neuroscience and Center for Brain Immunology and Glia (BIG Center). “Together, these findings suggest that STING drives detrimental immune responses in the brain that exacerbate neuronal damage and contribute to cognitive decline in Alzheimer’s disease.”

Promising Treatment Target

While scientists have been investigating other molecules thought to be important in Alzheimer’s, STING makes for a particularly attractive target for developing new treatments, the UVA Health researchers say. That’s because blocking STING appears to slow both the buildup of amyloid plaques and the development of tau tangles, the two leading candidates for the cause of Alzheimer’s. Other molecules lack that robust involvement, and, further, could be targeted only at very specific – and very limited – stages in the disease’s progression.

“We are only beginning to understand the complex role of innate immune activation in the brain, and this is especially true in both normal and pathological aging,” Thanos said. “If we can pinpoint which cells and signals sustain that activation, we will be in a much better position to intervene effectively in disease.”

While Lukens’ pioneering research has opened new doors in the fight against Alzheimer’s, much more work will need to be done to translate the findings into treatments. For example, scientists will need to better understand STING’s roles in the body – such as in the immune system’s response to cancer – to ensure any new treatment doesn’t cause unwanted side effects.

But those are the types of big questions that Lukens and his collaborators at the Harrison Family Translational Research Center are eager to tackle as part of their efforts to fast-track new treatments and, eventually, they hope, cures.

“Our hope is that this work moves us close to finding safer and more effective ways to protect the aging brain, as there is an urgent need for treatments that can slow or prevent neuronal damage in Alzheimer’s,” Lukens said. “Shedding light on how STING contributes to that damage may help us target similar molecules and ultimately develop effective disease-modifying treatments.”

Source: University of Virginia Health System

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The Hidden Connection Between Herpes and Alzheimer’s

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A new study has uncovered a surprising link between Alzheimer’s disease and Herpes Simplex Virus-1 (HSV-1).

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

A new study led by Dr Or Shemesh at the Hebrew University of Jerusalem has uncovered a surprising connection between Alzheimer’s disease and the Herpes Simplex Virus-1 (HSV-1). The research team used advanced techniques to identify 19 HSV-1-related proteins in the brains of people with Alzheimer’s, across all stages of the disease. This discovery, published in Cell Reports, strengthens the growing evidence that infections like HSV-1 might play a role in the development and progression of Alzheimer’s.

One key finding was the increased activity of a herpesvirus protein called ICP27, which became more prominent as the disease advanced. This protein was found to occupy the same space as tau, a brain protein that becomes harmful when it undergoes changes in Alzheimer’s disease, but it did not appear near amyloid plaques, another hallmark of the illness. This suggests that HSV-1 may directly affect tau and contribute to the changes seen in Alzheimer’s.

The team’s experiments with human brain organoids derived from stem cells revealed that HSV-1 infection can increase tau modifications at specific sites linked to Alzheimer’s disease.

Remarkably, these modifications seem to help protect brain cells early on by reducing the amount of virus and preventing cell death. However, as the disease progresses, these same processes may contribute to the brain damage associated with Alzheimer’s. The study also highlighted the role of Alzheimer’s pathologies as part of the brain’s natural immune system in this process, focusing on a pathway called cGAS-STING, which influences tau changes.

Dr Shemesh explained, “Our research shows how HSV-1 interacts with the brain and influences the pathologies of Alzheimer’s disease. Early on, the changes in tau may protect brain cells by limiting the virus, but as the disease advances, these same changes could lead to more harm and accelerate neurodegeneration.”

This study provides new insights into how infections and the brain’s immune response may be involved in Alzheimer’s disease. It suggests that targeting viral activity or modifying the immune system’s response could offer new treatment possibilities. While more research is needed to fully understand these processes, these findings open the door to innovative ways to slow or stop the progression of this devastating disease.

The research paper titled “Anti-Herpetic Tau Preserves Neurons vis the cGAS-STING-TBK1 Pathway in Alzheimer’s Disease” is now available in Cell Reports and can be accessed at https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01460-8 

Source: The Hebrew University of Jerusalem

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Alzheimer’s Drug Lecanemab Well Tolerated in Real-world Use

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Side effects of lecanemab are manageable, study finds

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The Food and Drug Administration’s approval in 2023 of lecanemab – a novel Alzheimer’s therapy shown in clinical trials to modestly slow disease progression – was met with enthusiasm by many in the field as it represented the first medication of its kind able to influence the disease. But side effects of brain swelling and bleeding emerged during clinical trials that have left some patients and physicians hesitant about the treatment. [Especially considering its $26 500 per year cost – Ed.]

Medications can have somewhat different effects once they are released into the real world with broader demographics. Researchers at Washington University School of Medicine in St. Louis set out to study the adverse events associated with lecanemab treatment in their clinic patients and found that significant adverse events were rare and manageable.

Consistent with the results from carefully controlled clinical trials, researchers found that only 1% of patients experienced severe side effects that required hospitalisation. Patients in the earliest stage of Alzheimer’s with very mild symptoms experienced the lowest risk of complications, the researchers found, helping to inform patients and clinicians as they navigate discussions about the treatment’s risks.

The retrospective study, published in JAMA Neurology, focused on 234 patients with very mild or mild Alzheimer’s disease who received lecanemab infusions in the Memory Diagnostic Center at WashU Medicine, a clinic that specialises in treating patients with dementia.

“This new class of medications for early symptomatic Alzheimer’s is the only approved treatment that influences disease progression,” said Barbara Joy Snider, MD, PhD, a professor of neurology and co-senior author on the study. “But fear surrounding the drug’s potential side effects can lead to treatment delays. Our study shows that WashU Medicine’s outpatient clinic has the infrastructure and expertise to safely administer and care for patients on lecanemab, including the few who may experience severe side effects, leading the way for more clinics to safely administer the drug to patients.”

Lecanemab is an antibody therapy that clears amyloid plaque proteins, extending independent living by 10 months, according to a recent study led by WashU Medicine researchers. Because amyloid accumulation is the first step in the disease, doctors recommend the drug for people in the early stage of Alzheimer’s, with very mild or mild symptoms. The researchers found that only 1.8% of patients with very mild Alzheimer’s symptoms developed any adverse symptoms from treatment compared with 27% of patients with mild Alzheimer’s.

“Patients with the very mildest symptoms of Alzheimer’s will likely have the greatest benefit and the least risk of adverse events from treatment,” said Snider, who led clinical trials for lecanemab at WashU Medicine. “Hesitation and avoidance can lead patients to delay treatment, which in turn increase the risk of side effects. We hope the results help reframe the conversations between physicians and patients about the medication’s risks.”

Hesitation around lecanemab stems from a side effect known as amyloid-related imaging abnormalities, or ARIA. The abnormalities, which typically only affect a very small area of the brain, appear on brain scans and indicate swelling or bleeding. In clinical trials of lecanemab, 12.6% of participants experienced ARIA and most cases were asymptomatic and resolved without intervention. A small percentage (2.8%) experienced symptoms such as headaches, confusion, nausea and dizziness. Occasional deaths have been linked to lecanemab in an estimated 0.2% of patients treated.

The Memory Diagnostic Center began treating patients with lecanemab in 2023 after the drug received full FDA approval. Patients receive the medication via infusions every two weeks in infusion centers. As part of each patient’s care, WashU Medicine doctors regularly gather sophisticated imaging to monitor the brain, which can detect bleeding and swelling with great sensitivity. Lecanemab is discontinued in patients with symptoms from ARIA or significant ARIA without symptoms, and the rare patients with severe ARIA are treated with steroids in the hospital.

In looking back on their patients’ outcomes, the authors found the extent of side effects aligned with those of the trials – most of the clinic’s cases of ARIA were asymptomatic and only discovered on sensitive brain scans used to monitor brain changes. Of the 11 patients who experienced symptoms from ARIA, the effects largely resolved within a few months and no patients died.

“Most patients on lecanemab tolerate the drug well,” said Suzanne Schindler, MD, PhD, an associate professor of neurology and a co-senior author of the study. “This report may help patients and providers better understand the risks of treatment, which are lower in patients with very mild symptoms of Alzheimer’s.”

Source: WashU Medicine

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HIV Drugs May Offer ‘Substantial’ Alzheimer’s Protection

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

UVA Health scientists are calling for clinical trials testing the potential of HIV drugs called NRTIs to prevent Alzheimer’s disease after discovering that patients taking the drugs are substantially less likely to develop the memory-robbing condition.

The researchers, led by UVA’s Jayakrishna Ambati, MD, previously identified a possible mechanism by which the drugs could prevent Alzheimer’s. That promising finding prompted them to analyse two of the nation’s largest health insurance databases to evaluate Alzheimer’s risk among patients prescribed the medications. In one, the risk of developing Alzheimer’s decreased 6% every year the patients were taking the drugs. In the other, the annual decrease was 13%.

“It’s estimated that over 10 million people around the world develop Alzheimer’s disease annually,” said Ambati, founding director of UVA’s Center for Advanced Vision Science and the DuPont Guerry III Professor in the School of Medicine’s Department of Ophthalmology. “Our results suggest that taking these drugs could prevent approximately 1 million new cases of Alzheimer’s disease every year.”

NRTIs restrain inflammasomes

NRTIs, or nucleoside reverse transcriptase inhibitors, are used to prevent the HIV virus from replicating inside the body. But Ambati and his team previously determined that the drugs can also prevent the activation of inflammasomes, important agents of our immune system. These proteins have been implicated in the development of Alzheimer’s disease, so Ambati and his colleagues wanted to see if patients taking the inflammasome-blocking drugs were less likely to develop Alzheimer’s.

To do that, they reviewed 24 years of patient data contained in the U.S. Veterans Health Administration Database – made up heavily of men – and 14 years of data in the MarketScan database of commercially insured patients, which offers a broader representation of the population. They looked for patients who were at least 50 years old and were taking medications for either HIV or hepatitis B, another disease treated with NRTIs. They excluded patients with a previous Alzheimer’s diagnosis.

In total, the researchers identified more than 270 000 patients who met the study criteria and then analysed how many went on to develop Alzheimer’s. Even after adjusting for factors that might cloud the results, such as whether patients had pre-existing medical conditions, the researchers determined that the reduction in risk among patients on NRTIs was “significant and substantial,” they report in a new scientific paper.

The researchers note that patients taking other types of HIV medications did not show the same reduction in Alzheimer’s risk as those on NRTIs. Based on that, they say that NRTIs warrant clinical testing to determine their ability to ward off Alzheimer’s. 

If successful, the benefits could be tremendous, as Alzheimer’s rates are climbing dramatically. Nearly 7 million Americans are living with the disease today, but that number is expected to climb to 13 million by 2050. Further, the estimated annual cost of care for Alzheimer’s and other dementias could rise from $360 billion to almost $1 trillion, the Alzheimer’s Association reports.

“We have also developed a new inflammasome-blocking drug called K9, which is a safer and more effective version of NRTIs,” Ambati said. “This drug is already in clinical trials for other diseases, and we plan to also test K9 in Alzheimer’s disease.”

Source: University of Virginia Health

Categories : Metabolic Disorders Neurodegenerative DiseasesTags :

Popular Diabetes Drugs may Protect Against Alzheimer’s Disease

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

A study led by researchers in the University of Florida College of Pharmacy has found that a pair of popular glucose-lowering medications may have protective effects against the development of Alzheimer’s disease and related dementias in patients with Type 2 diabetes.

In research published in JAMA Neurology on April 7, UF researchers studied Medicare claims data of older adults with Type 2 diabetes to assess the association among glucagon-like peptide-1 receptor agonists, or GLP-1RAs, sodium-glucose cotransporter-2 inhibitors, or SGLT2is, and the risk of Alzheimer’s disease and related dementias.

The research is supported by funding from the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases, both part of the National Institutes of Health.

The data showed a statistically significant association between a lower risk of Alzheimer’s and the use of GLP-1RAs and SGLT2is compared with other glucose-lowering medications. According to the researchers, the findings indicated that the two drugs may have neuroprotective effects for people without diabetes and may help slow the rate of cognitive decline in Alzheimer’s patients.

Serena Jingchuan Guo, MD, PhD, an assistant professor of pharmaceutical outcomes and policy and the study’s senior author, said these findings may point to new therapeutic uses for drugs commonly used to treat Type 2 diabetes and obesity.

“It’s exciting that these diabetes medications may offer additional benefits, such as protecting brain health,” Guo said. “Based on our research, there is promising potential for GLP-1RAs and SGLT2is to be considered for Alzheimer’s disease prevention in the future. As use of these drugs continues to expand, it becomes increasingly important to understand their real-world benefits and risks across populations.”

As the study only included patients with Type 2 diabetes, Guo said next steps include evaluating the effects of the two drugs in broader populations by using recent, real-world data that captures their growing use in clinical settings.

“Future research should focus on identifying heterogeneous treatment effects – specifically, determining which patients are most likely to benefit and who may be at greater risk for safety concerns,” Guo said.

Source: University of Florida

Categories : Neurodegenerative Diseases NeurologyTags :

Head Trauma may Activate Latent Viruses, Leading to Neurodegeneration

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In sports, the connection between head injuries and neurodegenerative diseases such as chronic traumatic encephalopathy, Alzheimer’s disease, and Parkinson’s disease is now well recognised.

Researchers at Tufts University and Oxford University have now uncovered mechanisms that may connect the dots between trauma events and the emergence of disease. They point to latent viruses lurking in most of our brains that may be activated by the jolt, leading to inflammation and accumulating damage that can occur over the ensuing months and years. 

The results suggest the use of antiviral drugs as potential early preventive treatments post-head injury. The findings are published in a study in Science Signaling.

The microbiome aids in digestion, immune system development, and protection against harmful pathogens. 

But the microbiome also includes dozens of viruses that swarm within our bodies at any given time. Some of these can be potentially harmful, but simply lie dormant within our cells. Herpes simplex virus 1 (HSV-1), found in over 80% of people, and varicella-zoster virus, found in 95% of people, are known to make their way into the brain and sleep within our neurons and glial cells.

Dana Cairns, GBS12, research associate in the Department of Biomedical Engineering and lead author of the study, had found evidence in earlier studies suggesting that activation of HSV-1 from its dormant state triggers the signature symptoms of Alzheimer’s disease in lab models of brain tissue: amyloid plaques, neuronal loss, inflammations, and diminished neural network functionality.

“In that study, another virus – varicella – created the inflammatory conditions that activated HSV-1,” said Cairns. “We thought, what would happen if we subjected the brain tissue model to a physical disruption, something akin to a concussion? Would HSV-1 wake up and start the process of neurodegeneration?”

The link between HSV-1 and Alzheimer’s disease was first suggested by co-author Ruth Itzhaki, visiting professorial fellow at Oxford University, who more than 30 years ago identified the virus in a high proportion of brains from the elderly population. Her subsequent studies suggested that the virus can be reactivated in the brain from a latent state by events such as stress or immunosuppression, ultimately leading to neuronal damage.

Blows to Brain-like Tissue

In the current study, the researchers used a lab model that reconstructs the environment of the brain to better understand how concussions may set off the first stages of virus reactivation and neurodegeneration.

The brain tissue model consists of a 6mm-wide donut-shaped sponge-like material made of silk protein and collagen suffused with neural stem cells, which are then coaxed into mature neurons, growing axons and dendrite extensions and forming a network. Glial cells also emerge from the stem cells to help mimic the brain environment and nurture the neurons.

The neurons communicate with each other through their extensions similarly to how they would communicate in a brain. And just like cells in the brain, they can carry within them the DNA of dormant HSV-1 virus.  

After enclosing the brain-like tissue in a cylinder and giving it a sudden jolt atop a piston, mimicking a concussion, Cairns examined the tissue under the microscope over time. Some of the tissue models had neurons with HSV-1, and some were virus-free. 

Following the controlled blows, she observed that the infected cells showed re-activation of the virus, and shortly after that the signature markers of Alzheimer’s disease, including amyloid plaques, p-tau (a protein that creates fiber-like “tangles” in the brain), inflammation, dying neurons, and a proliferation of glial cells called gliosis.

More strikes with the pistons on the tissue models mimicking repetitive head injuries led to the same reactions, which were even more severe. Meanwhile, the cells without HSV-1 showed some gliosis, but none of the other markers of Alzheimer’s disease.

The results were a strong indicator that athletes suffering concussions could be triggering reactivation of latent infections in the brain that can lead to Alzheimer’s disease. Epidemiological studies have shown that multiple blows to the head can lead to doubling or even greater chances of having a neurodegenerative condition months or years down the line.
 
“This opens the question as to whether antiviral drugs or anti-inflammatory agents might be useful as early preventive treatments after head trauma to stop HSV-1 activation in its tracks, and lower the risk of Alzheimer’s disease,” said Cairns.

The problem goes far beyond the concerns for athletes. Traumatic brain injury is one of the most common causes of disability and death in adults, affecting about 69 million people worldwide each year, at an economic cost estimated at $400 billion annually.

“The brain tissue model takes us to another level in investigating these connections between injury, infection, and Alzheimer’s disease,” said David Kaplan, Stern Family Endowed Professor of Engineering at Tufts.

“We can re-create normal tissue environments that look like the inside of a brain, track viruses, plaques, proteins, genetic activity, inflammation and even measure the level of signalling between neurons,” he said. “There is a lot of epidemiological evidence about environmental and other links to the risk of Alzheimer’s. The tissue model will help us put that information on a mechanistic footing and provide a starting point for testing new drugs.”

Source: Tufts University

Categories : NeurologyTags :

An Arthritis Drug Might Unlock Lasting Relief from Epilepsy and Seizures

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A drug typically prescribed for arthritis halts brain-damaging seizures in mice that have a condition like epilepsy, according to researchers at the University of Wisconsin–Madison. The drug, called tofacitinib, also restores short-term and working memory lost to epilepsy in the mice and reduces inflammation in the brain caused by the disease.

If the drug proves viable for human patients, it would be the first to provide lasting relief from seizures even after they stopped taking it.

“It ticks all the boxes of everything we’ve been looking for,” says Avtar Roopra, a neuroscience professor in the UW–Madison School of Medicine and Public Health and senior author of the study, which appears in Science Translational Medicine.

Epilepsy is one of the most common neurological diseases, afflicting more than 50 million people around the world. While there are many known causes, the disease often appears after an injury to the brain, like a physical impact or a stroke.

Some days, months or even years after the injury, the brain loses the ability to calm its own activity. Normally balanced electrical activity through the brain goes haywire.

“The system revs up until all the neurons are firing all the time, synchronously,” says Roopra. “That’s a seizure that can cause massive cell death.”

And the seizures repeat, often at random intervals, forever. Some drugs have been useful in addressing seizure symptoms, protecting patients from some of the rampant inflammation and memory loss, but one-third of epilepsy patients do not respond to any known drugs, according to Olivia Hoffman, lead author of the study and a postdoctoral researcher in Roopra’s lab. The only way to stop the most damaging seizures has been to remove a piece of the brain where disruptive activity starts.

On their way to identifying tofacitinib’s potential in epilepsy, Hoffman and co-authors used relatively new data science methods to sift through the way thousands of genes were expressed in millions of cells in the brains of mice with and without epilepsy. They found a protein called STAT3, key to a cell signaling pathway called JAK, at the centre of activity in the seizure-affected mouse brains.

“When we did a similar analysis of data from brain tissue removed from humans with epilepsy, we found that was also driven by STAT3,” Hoffman says.

Meanwhile, Hoffman had unearthed a study of tens of thousands of arthritis patients in Taiwan aimed at describing other diseases associated with arthritis. It turns out, epilepsy was much more common among those arthritis patients than people without arthritis — but surprisingly less common than normal for the arthritis patients who had been taking anti-inflammatory drugs for more than five-and-a-half years.

“If you’ve had rheumatoid arthritis for that long, your doctor has probably put you on what’s called a JAK-inhibitor, a drug that’s targeting this signaling pathway we’re thinking is really important in epilepsy,” Hoffman says.

The UW researchers ran a trial with their mice, dosing them with the JAK-inhibitor tofacitinib following the administration of a brain-damaging drug that puts them on the road to repeated seizures. Nothing happened. The mice still developed epilepsy like human patients.

Remember, though, that epilepsy doesn’t often present right after a brain-damaging event. It can take years. In the lab mice, there’s usually a lull of weeks of relatively normal time between the brain damage and what the researchers call “reignition” of seizures. If it’s not really epilepsy until reignition, what if they tried the drug then? They devised a 10-day course of tofacitinib to start when the mouse brains fell out of their lull and back into the chaos of seizures.

“Honestly, I didn’t think it was going to work,” Hoffman says. “But we believe that initial event sort of primes this pathway in the brain for trouble. And when we stepped in at that reignition point, the animals responded.”

The drug worked better than they could have imagined. After treatment, the mice stayed seizure-free for two months, according to the paper. Collaborators at Tufts University and Emory University tried the drug with their own mouse models of slightly different versions of epilepsy and got the same, seizure-free results.

Roopra’s lab has since followed mice that were seizure-free for four and five months. And their working memory returned.

“These animals are having many seizures a day. They cannot navigate mazes. Behaviourally, they are bereft. They can’t behave like normal mice, just like humans who have chronic epilepsy have deficits in learning and memory and problems with everyday tasks,” Roopra says. “We gave them that drug, and the seizures disappear. But their cognition also comes back online, which is astounding. The drug appears to be working on multiple brain systems simultaneously to bring everything under control, as compared to other drugs, which only try to force one component back into control.”

Because tofacitinib is already FDA-approved as safe for human use for arthritis, the path from animal studies to human trials may be shorter than it would be for a brand-new drug. The next steps toward human patients largely await NIH review of new studies, which have been paused indefinitely amid changes at the agency.

For now, the researchers are focused on trying to identify which types of brain cells are shifted back to healthy behavior by tofacitinib and on animal studies of even more of the many types of epilepsy. Hoffman and Roopra have also filed for a patent on the use of the drug in epilepsy.

Source: University of Wisconsin-Madison

Categories : Neurodegenerative Diseases NeurologyTags :

More Evidence Shows that 40Hz Gamma Stimulation is Beneficial for Brain Health

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A decade of studies from labs around the world provide a growing evidence base that increasing the power of the brain’s gamma rhythms could help fight Alzheimer’s, and perhaps other, neurological diseases.

Source: Pixabay

A decade after scientists in The Picower Institute for Learning and Memory at MIT first began testing whether sensory stimulation of the brain’s 40Hz “gamma” frequency rhythms could treat Alzheimer’s disease in mice, a growing evidence base supporting the idea that it can improve brain health – in humans as well as animals – has emerged from the work of labs all over the world. A new review article in PLOS Biology describes the state of research so far and presents some of the fundamental and clinical questions at the forefront of the non-invasive gamma stimulation now.

“As we’ve made all our observations, many other people in the field have published results that are very consistent,” said Li-Huei Tsai, Picower Professor at MIT, director of MIT’s Aging Brain Initiative, and senior author of the new review with postdoc Jung Park. “People have used many different ways to induce gamma including sensory stimulation, transcranial alternating current stimulation or transcranial magnetic stimulation, but the key is delivering stimulation at 40 Hz. They all see beneficial effects.”

A decade of discovery at MIT

Starting with a paper in Nature in 2016, a collaboration led by Tsai has produced a series of studies showing that 40Hz stimulation via light, sound, a combination of the two, or tactile vibration reduces hallmarks of Alzheimer’s pathology such as amyloid and tau proteins, prevents neuron death, decreases synapse loss, and sustains memory and cognition in various Alzheimer’s mouse models. The collaboration’s investigations of the underlying mechanisms that produce these benefits has so far identified specific cellular and molecular responses in many brain cell types including neurons, microglia, astrocytes, oligodendrocytes and the brain’s blood vessels. Last year, for instance, the lab reported in Nature that 40Hz audio and visual stimulation induced interneurons in mice to increase release of the peptide VIP, prompting increased clearance of amyloid from brain tissue via the brain’s glymphatic “plumbing” system.

Meanwhile, at MIT and at the MIT spinoff company Cognito Therapeutics, phase II clinical studies have shown that people with Alzheimer’s exposed to 40Hz light and sound experienced a significant slowing of brain atrophy and improvements on some cognitive measures compared to untreated controls. Cognito, which has also measured significant preservation of white matter in volunteers, has been conducting a pivotal, nationwide phase III clinical trial of sensory gamma stimulation for more than a year.

“Neuroscientists often lament that it is a great time to have AD if you are a mouse,” Park and Tsai wrote in the review. “Our ultimate goal, therefore, is to translate GENUS discoveries into a safe, accessible, and non-invasive therapy for AD patients.” The MIT team often refers to 40Hz stimulation as “GENUS” for Gamma Entrainment Using Sensory Stimulation.

A growing field

As Tsai’s collaboration, which includes MIT colleagues Edward Boyden and Emery N. Brown, has published its results, many other labs have produced studies adding to the evidence that various methods of non-invasive gamma sensory stimulation can combat Alzheimer’s pathology. Among many examples cited in the new review, in 2024 a research team in China independently corroborated that 40Hz sensory stimulation increases glymphatic fluid flows in mice. In another example, a Harvard Medical School-based team in 2022 showed that 40Hz gamma stimulation using Transcranial Alternating Current Stimulation significantly reduced the burden of tau in three out of four human volunteers. And in another study involving more than 100 people, researchers in Scotland in 2023 used audio and visual gamma stimulation (at 37.5Hz) to improve memory recall.

Open questions

Amid the growing number of publications describing preclinical studies with mice and clinical trials with people, open questions remain, Tsai and Park acknowledge. The MIT team and others are still exploring the cellular and molecular mechanisms that underlie GENUS’s effects. Tsai said her lab is looking at other neuropeptide and neuromodulatory systems to better understand the cascade of events linking sensory stimulation to the observed cellular responses. Meanwhile the nature of how some cells, such as microglia, respond to gamma stimulation and how that affects pathology remains unclear, Tsai added.

Even with a national Phase III clinical trial underway, it is still important to investigate these fundamental mechanisms, Tsai said, because new insights into how non-invasive gamma stimulation affects the brain could improve and expand its therapeutic potential.

“The more we understand the mechanisms, the more we will have good ideas about how to further optimize the treatment,” Tsai said. “And the more we understand its action and the circuits it affects, the more we will know beyond Alzheimer’s disease what other neurological disorders will benefit from this.”

Indeed the review points to studies at MIT and other institutions providing at least some evidence that GENUS might be able to help with Parkinson’s disease, stroke, anxiety, epilepsy, and the cognitive side effects of chemotherapy and conditions that reduce myelin such as multiple sclerosis. Tsai’s lab has been studying whether it can help with Down syndrome as well.

The open questions may help define the next decade of GENUS research.

Source: Picower Institute at MIT

Categories : Neurodegenerative Diseases New Compounds and TreatmentsTags :

Noble Intentions: Xenon Gas might Protect against Alzheimer’s

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By Alchemist-hp (talk) (www.pse-mendelejew.de) – Own work, FAL

Most treatments being pursued today to protect against Alzheimer’s disease focus on amyloid plaques and tau tangles that accumulate in the brain, but new research from Mass General Brigham and Washington University School of Medicine in St. Louis points to a novel – and noble – approach: using xenon gas. The study found that xenon gas inhalation suppressed neuroinflammation, reduced brain atrophy, and increased protective neuronal states in mouse models of Alzheimer’s disease. Results are published in Science Translational Medicine, and a phase 1 clinical trial of the treatment in healthy volunteers will begin in early 2025.

“It is a very novel discovery showing that simply inhaling an inert gas can have such a profound neuroprotective effect,” said senior and co-corresponding author Oleg Butovsky, PhD, at Brigham and Women’s Hospital (BWH). “One of the main limitations in the field of Alzheimer’s disease research and treatment is that it is extremely difficult to design medications that can pass the blood-brain barrier – but senon gas does. We look forward to seeing this novel approach tested in humans.”

“It is exciting that in both animal models that model different aspects of Alzheimer’s disease, amyloid pathology in one model and tau pathology in another model, that Xenon had protective effects in both situations,” said senior and co-corresponding author David M. Holtzman, MD, from Washington University School of Medicine in St. Louis.

The causes of Alzheimer’s disease are not fully understood; there is currently no cure, and more effective treatments are desperately needed. Characterised by protein buildups in the brain, including tau and amyloid, Alzheimer’s disease disrupts nerve cell communication and causes progressive brain abnormalities that lead to neuronal damage and ultimately to death. Microglia, the brain’s primary and most prominent immune cells, act as ‘first responders’ when something goes awry in the brain, and they play a key role in regulating brain function in all phases of development. Microglial dysregulation is a key component of Alzheimer’s disease. Butovsky’s lab previously designed a way to study how microglia respond to neurodegeneration and confirmed that a specific phenotype of microglia can be modulated in a way that is protective in Alzheimer’s disease.

In this study, mouse models of Alzheimer’s disease were treated with xenon gas that has been used in human medicine as an anesthetic and as a neuroprotectant for treating brain injuries. Xenon gas penetrates the blood-brain barrier, passing from the bloodstream directly into the fluid surrounding the brain. The team found that xenon gas inhalation reduced brain atrophy and neuroinflammation and improved nest-building behaviours in the Alzheimer’s disease mouse models. It also induced and increased a protective microglial response that is associated with clearing amyloid and improving cognition. Together, these findings identify the promising potential of xenon inhalation as a therapeutic approach that could modify microglial activity and reduce neurodegeneration in Alzheimer’s disease.

The clinical trial at Brigham and Women’s Hospital, which will initially only enrol healthy volunteers, is set to begin in the next few months.

As early phases of the clinical trial get underway to establish safety and dosage, the research team plans to continue to study the mechanisms by which xenon gas achieves its effects in addition to its potential for treating other diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and eye diseases that involve the loss of neurons. The team is also devising technologies to help use xenon gas more efficiently as well as potentially recycle it.

“If the clinical trial goes well, the opportunities for the use of Xenon gas are great,” said co-author Howard Weiner, MD, co-director of the Ann Romney Center for Neurologic Diseases at BWH and principal investigator of the upcoming clinical trial. “It could open the door to new treatments for helping patients with neurologic diseases.”

Source: Mass General Brigham

Categories : Neurodegenerative DiseasesTags :

Herpes Virus Might Drive Alzheimer’s Pathology, Study Suggests

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

University of Pittsburgh researchers uncovered a surprising link between Alzheimer’s disease and herpes simplex virus-1 (HSV-1), suggesting that viral infections may play a role in the disease. The study results were published in Cell Reports.

The study also revealed how tau protein, often viewed as harmful in Alzheimer’s, might initially protect the brain from the virus but contribute to brain damage later. These findings could lead to new treatments targeting infections and the brain’s immune response.

“Our study challenges the conventional view of tau as solely harmful, showing that it may initially act as part of the brain’s immune defence,” said senior author Or Shemesh, assistant professor in the Department of Ophthalmology at Pitt. “These findings emphasise the complex interplay between infections, immune responses and neurodegeneration, offering a fresh perspective and potential new targets for therapeutic development.”

The scientists identified forms of HSV-1-related proteins in Alzheimer’s brain samples, with greater amounts of viral proteins co-localised with tangles of phosphorylated tau—one of the hallmarks of Alzheimer’s pathology—in brain regions especially vulnerable to Alzheimer’s across disease stages.

Further studies on miniature models of human brains in a Petri dish suggested that HSV-1 infection could modulate levels of brain tau protein and regulate its function, a protective mechanism that seemed to decrease post-infection death of human neurons.

While the precise mechanisms by which HSV-1 influences tau protein and contributes to Alzheimer’s disease are still unknown, Shemesh and his colleagues plan to explore those questions in future research. They aim to test potential therapeutic strategies that target viral proteins or fine-tune the brain’s immune response and investigate whether similar mechanisms are involved in other neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis.

Source: University of Pittsburgh