Artificial Molecule With Superpowers

When scientists discovered DNA and learned how to control it, not only science but society was revolutionized. Today researchers and the medical industry routinely create artificial DNA structures for many purposes, including diagnosis and treatment of diseases. Now an international research team reports to have created a powerful supermolecule with the potential to further revolutionize science. The work is published in Nature Communications . Authors are from University of Southern Denmark (DK), Kent State University (USA), Copenhagen University (Denmark), Oxford University (UK) and ATDBio (UK). Lead authors are Chenguang Lou, associate professor, University of Southern Denmark and Hanbin Mao, professor, Kent State University, USA.

The researchers describe their supermolecule as a marriage between DNA and peptides

DNA is one of the most important biomolecules, and so are peptides; peptide structures are used, among other things, to create artificial proteins and various nanostructures. If you combine these two, as we have, you get a very powerful molecular tool, that may lead to the next generation of nanotechnology; it may allow us to make more advanced nanostructures, for example, for detecting diseases, says corresponding author Chenguang Lou, associate professor at Department of Physics, Chemistry and Pharmacy, University of Southern Denmark. According to the researchers, another example is that this marriage of peptides to DNA can be used to create artificial proteins, which will be more stable and thus more reliable to work with than natural proteins, which are vulnerable to heat, UV, chemical reagents, etc.

Our next step will be to investigate whether it can be used to explain the cause of Alzheimer’s disease in which malfunctional peptides are culprits, says the other corresponding author, Hanbin Mao, professor at Chemistry and Biochemistry, Kent State University. The research work reports the mechanical properties of a new structure composed of three-stranded DNA structures and three-stranded peptide structures. It may sound simple, but it is far from. It is rare in Nature that DNA and peptide structures are chemically linked like this new structure is. In Nature, they often behave like cats and dogs, though some key interactions are essential to any living organisms. One possible reason for this is their so-called chirality – sometimes also described as handedness.

All biological structures, from molecules to the human body, have a fixed chirality; think of our heart, which is always positioned in the left side of our body. DNA is always right-handed and peptides are always left-handed, so trying to combine them is a highly challenging task. Imagine you want to stack your two hands by matching each finger while both palms face the same direction. You will find out it is impossible to do it. You can only do this if you can trick your two hands into having the same chirality, says Hanbin Mao. This is what the research team has done; tricked the chirality. They have changed the peptide chirality from left to right, so it fits with the chirality of the DNA and works with it instead of repelling it.

This is the first study to show that the chirality of DNA and peptide structures can communicate and interact, when their handedness is changed, says Chenguang Lou. The researchers also report to be the first to provide an answer to why the biological world is chiral: The answer is energy: the chiral world requires the lowest energy to maintain, therefore it is most stable, says Hanbin Mao. In other words: Nature will always seek to spend as little energy as possible.

Source: https://www.sdu.dk/

Viagra Users Are 69% Less Likely to Develop Alzheimer’s

Viagra could be a useful treatment against Alzheimer’s disease, according to a US study. Alzheimer’s disease, the most common form of age-related dementia, affects hundreds of millions of people worldwide. Despite mounting numbers of cases, however, there is currently no effective treatment.

Using a large gene-mapping network, researchers at the Cleveland Clinic integrated genetic and other data to determine which of more than 1,600 Food and Drug Administration-approved drugs could be an effective treatment for Alzheimer’s disease. They gave higher scores to drugs that target both amyloid and tau – two hallmarks of Alzheimer’s – compared with drugs that targeted just one or the other.

US scientists say users of sildenafil – the generic name for Viagra – are 69% less likely to develop the form of dementia than non-users

“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” said Dr Feixiong Cheng, the study lead.

Researchers then used a database of claims from more than 7 million people in the US to examine the relationship between sildenafil and Alzheimer’s disease outcomes by comparing sildenafil users to non-users.

They found sildenafil users were 69% less likely to develop Alzheimer’s disease than non-sildenafil users after six years of follow-up. To further explore the drug’s potential effect on Alzheimer’s disease, researchers developed a lab model that showed that sildenafil increased brain cell growth and targeted tau proteins, offering insights into how it might influence disease-related brain changes. Cheng cautioned that the study does not demonstrate a causal relationship between sildenafil and Alzhemer’s disease. Randomised clinical trials involving both sexes with a placebo control were needed to determine sildenafil’s efficacy, he said.

Dr Ivan Koychev, a senior clinical researcher at the University of Oxford, who was not involved in the study, said it was “an exciting development” because “it points to a specific drug which may offer a new approach to treating the condition”.

Prof Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, said there were several important limitations to consider. “While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease.”

Dr Susan Kohlhaas, director of research at Alzheimer’s Research UK, said: “Being able to repurpose a drug already licensed for other health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner. “Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease. The only way to test this would be in a large-scale clinical trial measuring sildenafil effect against the usual standard of care.”

The findings were published in Nature Aging.

Source: https://www.theguardian.com/

Nasal Vaccine to prevent Alzheimer’s

Brigham and Women’s Hospital will test the safety and efficacy of a nasal vaccine aimed at preventing and slowing Alzheimer’s disease, the Boston hospital announced Tuesday. The start of the small, Phase I clinical trial comes after nearly 20 years of research led by Howard L. Weiner, MD, co-director of the Ann Romney Center for Neurologic Diseases at the hospital.

The trial will include 16 participants between the ages of 60 and 85, all with early symptomatic Alzheimer’s but otherwise generally healthy. They will receive two doses of the vaccine one week apart, the hospital said in a press release. The participants will enroll from the Ann Romney Center.

A Phase I clinical trial is designed to establish the safety and dosage for a potential new medication. If it goes well, a much larger trial would be needed to test its effectiveness. The vaccine uses a substance called Protollin, which stimulates the immune system. “Protollin is designed to activate white blood cells found in the lymph nodes on the sides and back of the neck to migrate to the brain and trigger clearance of beta amyloid plaques — one of the hallmarks of AD [Alzheimer’s disease],” the hospital explains. It notes that Protollin has been found to be safe in other vaccines.

The launch of the first human trial of a nasal vaccine for Alzheimer’s is a remarkable milestone,” said Weiner in the hospital’s press release. “Over the last two decades, we’ve amassed preclinical evidence suggesting the potential of this nasal vaccine for AD. If clinical trials in humans show that the vaccine is safe and effective, this could represent a nontoxic treatment for people with Alzheimer’s, and it could also be given early to help prevent Alzheimer’s in people at risk.”

The researchers say they aim to “determine the safety and tolerability of the nasal vaccine” in the trial and observe how Protollin affects participants’ immune response, including how it affects their white blood cells.

The immune system plays a very important role in all neurologic diseases,” Weiner added. “And it’s exciting that after 20 years of preclinical work, we can finally take a key step forward toward clinical translation and conduct this landmark first human trial.”

Source: brighamandwomens.org
AND
https://www.cbsnews.com/

Dementia Test on IPad

A dementia diagnosis usually starts with a family member noticing that something isn’t quite right: a partner becoming forgetful, a normally placid parent losing their temper more often. From there, there are doctor’s appointments—memory and behavior tests that haven’t changed in years, brain scans if the money is there, or one of the battery of new blood tests looking for the biomarkers of brain damage. And then: nothing.

Neurodegenerative diseases like dementia and Alzheimer’s are more feared than cancer and heart disease combined, according to a 2016 survey, and one of the most frightening things about them is how little we still know. There are no cures, and few effective treatments.

So you might question the benefits of a 5-minute test that can assess your risk of getting dementia before you show any symptoms. The Integrated Cognitive Assessment (ICA) test, developed by the British startup Cognetivity Neurosciences, has been granted Food and Drug Administration clearance to be marketed in the United States and is being trialled at several NHS trusts in the UK. But is there any point in taking a test for a disease you can’t do anything about?

The ICA is designed as a “semi-supervisedscreening test, says Cognetivity CEO Sina Habibi. It could form part of an annual health check-up for the over-50s, looking for the earliest signs of neurodegenerative disease before they become apparent in behavior.In the same way you look at blood pressure, you could look at the brain with a cognitive test to see if there’s something malfunctioning,” he says.

An early diagnosis could help people plan ahead and put their affairs in order—but arguably that’s something they should probably be doing anyway. Lifestyle tweaks such as eating less fat, exercising more, or drinking less can also reduce risk, particularly in vascular dementia, which is caused by poor blood supply to the brain and is therefore closely linked to heart health.

The procedure runs on an iPad. A zebra appears onscreen and then disappears, replaced by a railway bridge. There are flashes of beach scenes in black and white, and then a glimpse of an exotic bird, all interspersed with monochrome grids and fuzzy static—a captcha at warp speed. The user’s task is simple: They tap on the right side of the screen whenever they see an animal in one of the pictures, and on the left side when they don’t.

NeuroInflammation Critical in the Developement of Alzheimer’s

Doctors regard amyloid plaque lodged between the brain’s nerve cells and tangled tau protein fibers forming within the cells as the hallmark of Alzheimer’s disease. However, amyloid plaque — consisting of broken pieces of protein that clump together — is also present in the brains of older adults who do not develop Alzheimer’s, suggesting another factor is triggering the disease.

A new study finds that inflammation in the brain drives the progression from the presence of amyloid plaque and tau tangles to the onset of dementia and Alzheimer’s disease.
Lead author of the study, Dr. Tharick Pascoal, Ph.D., assistant professor of psychiatry and neurology at the University of Pittsburgh School of Medicine, PA, explains:

Many [older adults] have amyloid plaques in their brains but never progress to developing Alzheimer’s disease. We know that amyloid accumulation on its own is not enough to cause dementia — our results suggest that it is the interaction between neuroinflammation and amyloid pathology that unleashes tau propagation and eventually leads to widespread brain damage and cognitive impairment.”

While scientists have observed neuroinflammation in people with Alzheimer’s before, the new study reveals for the first time its critical role in the development of the disease. The research finds that activating the brain’s immune cells — its microglial cellspromotes the spread of tangled tau proteins that comprise amyloid plaque.

Heather M. Snyder, Ph.D., Alzheimer’s Association vice president of medical and scientific relations, who was not involved in the study, explained the purpose of neuroinflammation to Medical News Today. The Alzheimer’s Association contributed funding to the research.

Inflammation has an important role in fighting off infection and other pathogens in the body, including in the brain and central nervous system,” said Snyder. Microglia “help clear debris (damaged neurons, infections) from the brain.” “However,” adds Dr. Snyder, “a sustained inflammatory response, or a change from acute to chronic neuroinflammation, may contribute to the underlying biology of several neurodegenerative disorders.

Inflammation is not by itself associated with cognitive impairment, daid Dr. Pascoal. “However when neuroinflammation converges with amyloid pathology, the interaction potentiates tau pathology. As a consequence, the coexistence of these three processes in the brain — amyloid, neuroinflammation, and tau pathology — determines cognitive deterioration.”

Results suggest that the combination of anti-amyloid with anti-inflammatory therapies in the early stages of the disease, when the pathology of tau is still confined to the temporal cortex, would maximize the efficacy of these drugs.”

The study appears in Nature Medicine.

Source: https://www.medicalnewstoday.com/

New Algorithm Predicts Alzheimer’s with 99% accuracy

Researchers from Kaunas universities in Lithuania developed a deep learning-based method that can predict the possible onset of Alzheimer’s disease from brain images with an accuracy of over 99 per cent. The method was developed while analysing functional MRI images obtained from 138 subjects and performed better in terms of accuracy, sensitivity and specificity than previously developed methods.

According to World Health Organisation, Alzheimer’s disease is the most frequent cause of dementia, contributing to up to 70 per cent of dementia cases. Worldwide, approximately 24 million people are affected, and this number is expected to double every 20 years. Owing to societal ageing, the disease will become a costly public health burden in the years to come.

Medical professionals all over the world attempt to raise awareness of an early Alzheimer’s diagnosis, which provides the affected with a better chance of benefiting from treatment. This was one of the most important issues for choosing a topic for Modupe Odusami, a PhD student from Nigeria”, says Rytis Maskeliūnas, a researcher at the Department of Multimedia Engineering, Faculty of Informatics, Kaunas University of Technology (KTU), Odusami’s PhD supervisor. One of the possible Alzheimer’s first signs is mild cognitive impairment (MCI), which is the stage between the expected cognitive decline of normal ageing and dementia. Based on the previous research, functional magnetic resonance imaging (fMRI) can be used to identify the regions in the brain which can be associated with the onset of Alzheimer’s disease, according to Maskeliūnas. The earliest stages of MCI often have almost no clear symptoms, but in quite a few cases can be detected by neuroimaging.

However, although theoretically possible, manual analysing of fMRI images attempting to identify the changes associated with Alzheimer’s not only requires specific knowledge but is also time-consuming – application of Deep learning and other AI methods can speed this up by a significant time margin. Finding MCI features does not necessarily mean the presence of illness, as it can also be a symptom of other related diseases, but it is more of an indicator and possible helper to steer toward an evaluation by a medical professional.

Modern signal processing allows delegating the image processing to the machine, which can complete it faster and accurately enough. Of course, we don’t dare to suggest that a medical professional should ever rely on any algorithm one-hundred-per cent. Think of a machine as a robot capable of doing the most tedious task of sorting the data and searching for features. In this scenario, after the computer algorithm selects potentially affected cases, the specialist can look into them more closely, and at the end, everybody benefits as the diagnosis and the treatment reaches the patient much faster”, says Maskeliūnas, who supervised the team working on the model.

Source: https://en.ktu.edu/

FDA-approved Drugs Slow or Reverse Alzheimer’s

A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer’s disease, as well as existing drugs that have therapeutic potential against these targets.

The potential targets are defective proteins that lead to the buildup of amyloid in the brain, contributing to the onset of problems with memory and thinking that are the hallmark of Alzheimer’s. The 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers.

In addition, the experiments yielded seven drugs that may be useful for treating faulty proteins linked to Parkinson’s disease, six for stroke and one for amyotrophic lateral sclerosis (ALS).

Scientists have worked for decades to develop treatments for Alzheimer’s by targeting genes rooted in the disease process but have had little success. That approach has led to several dead ends because many of those genes don’t fundamentally alter proteins at work in the brain. The new study takes a different approach, by focusing on proteins in the brain, and other tissues, whose function has been altered.

In this study, we used human samples and the latest technologies to better understand the biology of Alzheimer’s disease,” said principal investigator Carlos Cruchaga, the Reuben Morriss III Professor of Neurology and a professor of psychiatry. “Using Alzheimer’s disease samples, we’ve been able to identify new genes, druggable targets and FDA-approved compounds that interact with those targets to potentially slow or reverse the progress of Alzheimer’s.”

The scientists focused on protein levels in the brain, cerebrospinal fluid (CSF) and blood plasma of people with and without Alzheimer’s disease. Some of the proteins were made by genes previously linked to Alzheimer’s risk, while others were made by genes not previously connected to the disease. After identifying the proteins, the researchers compared their results to several databases of existing drugs that affect those proteins.

The new study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is published in the journal Nature Neuroscience.

Source: https://source.wustl.edu/

LDL Receptor Identified as Therapeutic Target for Alzheimer’s

By the time people with Alzheimer’s disease start exhibiting difficulty remembering and thinking, the disease has been developing in their brains for two decades or more, and their brain tissue already has sustained damage. As the disease progresses, the damage accumulates, and their symptoms worsen.

Researchers at Washington University School of Medicine in St. Louis have found that high levels of a normal protein associated with reduced heart disease also protect against Alzheimer’s-like brain damage – at least in mice. The findings, published in Neuron, suggest that raising levels of the protein — known as low-density lipoprotein receptor (LDL receptor) — could potentially be a way to slow or stop cognitive decline.

The discovery of LDL receptor as a potential therapeutic target for dementia is surprising since the protein is much better known for its role in cholesterol metabolism. Statins and PCSK9 inhibitors, two groups of drugs widely prescribed for cardiovascular disease, work in part by increasing levels of LDL receptor in the liver and some other tissues. It is not known whether they affect LDL receptor levels in the brain.

There are not yet clearly effective therapies to preserve cognitive function in people with Alzheimer’s disease,” said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “We found that increasing LDL receptor in the brain strongly decreases neurodegeneration and protects against brain injury in mice. If you could increase LDL receptor in the brain with a small molecule or other approach, it could be a very attractive treatment strategy.”

The key to the importance of LDL receptor lies in a different protein, APOE, that also is linked to both cholesterol metabolism and Alzheimer’s disease. High cholesterol in the blood is associated with increased risk of Alzheimer’s disease, although the exact nature of the association is unclear.

During the long, slow development of Alzheimer’s disease, plaques of a protein called amyloid gradually accumulate in the brain. After many years, another brain protein called tau starts forming tangles that become detectable just before Alzheimer’s symptoms arise. The tangles are thought to be toxic to neurons, and their spread through the brain foretells the death of brain tissue and cognitive decline. First author Yang Shi, PhD, a postdoctoral researcher, and Holtzman previously showed that APOE drives tau-mediated degeneration in the brain by activating microglia, the brain’s cellular janitorial crew. Once activated, microglia can injure neural tissue in their zeal to clean up molecular debris.

Higher levels of LDL receptor limit the damage APOE can do in part by binding to APOE and degrading it. Higher levels of LDL receptor in the brain, therefore, should pull more APOE out of the fluid surrounding brain cells and mitigate damage even further, the researchers reasoned.

CRISPR Gene Editing Breakthrough could Treat many More Diseases

CRISPR gene editing already promises to fight diseases that were once thought unassailable, but techniques so far have required injecting the tools directly into affected cells. That’s not very practical for some conditions. However, there’s just been a breakthrough. NPR reports that researchers have published results showing that you can inject CRISPR-Cas9 into the bloodstream to make edits, opening the door to the use of gene editing for treating many common diseases.

The experimental treatment tackled a rare genetic disease, transthyretin amyloidosis. Scientists injected volunteers with CRISPR-loaded nanoparticles that were absorbed by the patients’ livers, editing a gene in the organ to disable production of a harmful protein. Levels of that protein plunged within weeks of the injection, saving patients from an illness that can rapidly destroy nerves and other tissues in their bodies.

The test involved just six people, and the research team still has to conduct long-term studies to check for possible negative effects. If this method proves viable on a large scale, though, it could be used to treat illnesses where existing CRISPR techniques aren’t practical, ranging from Alzheimer’s to heart disease.

There are some ethical considerations. Some are already wary about the potential for abusing CRISPR for ‘designer babies‘ and other less-than-altruistic purposes. Bloodstream injections would make it that much easier to perform dubious edits. If used properly, however, this new CRISPR method could avoid (or prevent) suffering that was once considered inevitable.

Source: https://www.npr.org/
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https://www.engadget.com/

Ultrasound Therapy for Alzheimer’s

One promising possibility when it comes to treating Alzheimer’s is the idea of using non-invasive ultrasound to take out toxic brain plaques, and a group of researchers in Australia have been at the cutting edge of this technology for a number of years. The scientists’ latest investigations have uncovered some surprising new ways this technique can improve cognition in mouse models of the disease, which they believe could have wider implications for restoring cognition in the elderly.

Led by Professor Jürgen Götz at the University of Queensland, the researchers behind this promising ultrasound therapy published some exciting early results in 2015. Initially, the idea was to use ultrasound in combination with gas-filled microbubbles to temporarily open the blood-brain barrier to allow in drugs that take out toxic amyloid and tau brain plaques that destroy synapses and are seen as key drivers of Alzheimer’s disease.

As it turned out, this technique proved an effective way to clear away the brain plaques without the need for any drugs, with the ultrasound activating microglial cells that could digest the plaques all on their own. The scientists then published a study in 2018 demonstrating how this technique could safely clear the toxic brain plaques and restore memory function in mouse models resembling human brains of 80 to 90 years old, and set their sights on human trials.

As they’ve continued to study this technique in mice, the scientists have continued to uncover new information about its effects on the brain, and how it might boost cognition. In newly published research, the team carried out new experiments on mouse models of brains with age-related deterioration, and found that it brought about yet further unexpected changes.

One of the physiological hallmarks of age-related cognitive decline is a deterioration in a type of signaling between neurons called long-term potentiation (LTP), which is associated with memory. The scientists were able to show that combining ultrasound with the microbubbles fully restored LTP in one region of the hippocampus. More interesting still, the ultrasound proved even more effective without the help of the microbubbles, not only restoring LTP but also improving the spatial learning deficits of the elderly mice by improving synaptic signaling and neurogenesis, among other physiological alterations.

Ultrasound may be a way to not just tackle brain plaques associated with Alzheimer’s, but also age-related cognitive decline in the broader population

The team’s ultrasound technique could serve as a two-pronged attack on Alzheimer’s, combining with microbubbles and plaque-busting agents to tackle the condition while simultaneously improving cognition via a separate pathway. And promisingly, the scientists believe the technique may one day prove a viable way to address age-related cognitive decline in the broader population.

Historically, we have been using ultrasound together with small gas-filled bubbles to open the almost-impenetrable blood-brain barrier and get therapeutics from the bloodstream into the brain,” Professor Götz says. “The entire research team was surprised by the remarkable restoration in cognition. We conclude therapeutic ultrasound is a non-invasive way to enhance cognition in the elderly.”

Source: https://qbi.uq.edu.au/