Experimental Drug Has Potential Against Alzheimer’s Disease

The drug reversed Alzheimer’s in mice through removing garbage from their brain cells. The research seems like a notable milestone against Alzheimer’s disease.

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Researchers at Albert Einstein College of Medicine have designed an experimental drug that reversed key symptoms of Alzheimer’s disease in mice. The drug works by reinvigorating a cellular cleaning mechanism that gets rid of unwanted proteins by digesting and recycling them. The study was published online today in the journal Cell.

“Discoveries in mice don’t always translate to humans, especially in Alzheimer’s disease,” said co-study leader Ana Maria Cuervo, M.D., Ph.D., the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases, professor of developmental and molecular biology, and co-director of the Institute for Aging Research at Einstein. “But we were encouraged to find in our study that the drop-off in cellular cleaning that contributes to Alzheimer’s in mice also occurs in people with the disease, suggesting that our drug may also work in humans.” In the 1990s, Dr. Cuervo discovered the existence of this cell-cleaning process, known as chaperone-mediated autophagy (CMA) and has published 200 papers on its role in health and disease.

CMA becomes less efficient as people age, increasing the risk that unwanted proteins will accumulate into insoluble clumps that damage cells. In fact, Alzheimer’s and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in patients’ brains. The Cell paper reveals a dynamic interplay between CMA and Alzheimer’s disease, with loss of CMA in neurons contributing to Alzheimer’s and vice versa. The findings suggest that drugs for revving up CMA may offer hope for treating neurodegenerative diseases.

Establishing CMA’s Link to Alzheimer’s

Dr. Cuervo’s team first looked at whether impaired CMA contributes to Alzheimer’s. To do so, they genetically engineered a mouse to have excitatory brain neurons that lacked CMA. The absence of CMA in one type of brain cell was enough to cause short-term memory loss, impaired walking, and other problems often found in rodent models of Alzheimer’s disease. In addition, the absence of CMA profoundly disrupted proteostasis — the cells’ ability to regulate the proteins they contain. Normally soluble proteins had shifted to being insoluble and at risk for clumping into toxic aggregates.

Dr. Cuervo suspected the converse was also true: that early Alzheimer’s impairs CMA. So she and her colleagues studied a mouse model of early Alzheimer’s in which brain neurons were made to produce defective copies of the protein tau. Evidence indicates that abnormal copies of tau clump together to form neurofibrillary tangles that contribute to Alzheimer’s. The research team focused on CMA activity within neurons of the hippocampus — the brain region crucial for memory and learning. They found that CMA activity in those neurons was significantly reduced compared to control animals.

What about early Alzheimer’s in people — does it block CMA too? To find out, the researchers looked at single-cell RNA-sequencing data from neurons obtained postmortem from the brains of Alzheimer’s patients and from a comparison group of healthy individuals. The sequencing data revealed CMA’s activity level in patients’ brain tissue. Sure enough, CMA activity was somewhat inhibited in people who had been in the early stages of Alzheimer’s, followed by much greater CMA inhibition in the brains of people with advanced Alzheimer’s.

“By the time people reach the age of 70 or 80, CMA activity has usually decreased by about 30% compared to when they were younger,” said Dr. Cuervo. “Most peoples’ brains can compensate for this decline. But if you add neurodegenerative disease to the mix, the effect on the normal protein makeup of brain neurons can be devastating. Our study shows that CMA deficiency interacts synergistically with Alzheimer’s pathology to greatly accelerate disease progression.”

A New Drug Cleans Neurons and Reverses Symptoms

In an encouraging finding, Dr. Cuervo and her team developed a novel drug that shows potential for treating Alzheimer’s. “We know that CMA is capable of digesting defective tau and other proteins,” said Dr. Cuervo. “But the sheer amount of defective protein in Alzheimer’s and other neurodegenerative diseases overwhelms CMA and essentially cripples it. Our drug revitalizes CMA efficiency by boosting levels of a key CMA component.”

In CMA, proteins called chaperones bind to damaged or defective proteins in cells of the body. The chaperones ferry their cargo to the cells’ lysosomes — membrane-bound organelles filled with enzymes, which digest and recycle waste material. To successfully get their cargo into lysosomes, however, chaperones must first “dock” the material onto a protein receptor called LAMP2A that sprouts from the membranes of lysosomes. The more LAMP2A receptors on lysosomes, the greater the level of CMA activity possible. The new drug, called CA, works by increasing the number of those LAMP2A receptors.

“You produce the same amount of LAMP2A receptors throughout life,” said Dr. Cuervo. “But those receptors deteriorate more quickly as you age, so older people tend to have less of them available for delivering unwanted proteins into lysosomes. CA restores LAMP2A to youthful levels, enabling CMA to get rid of tau and other defective proteins so they can’t form those toxic protein clumps.” (Also this month, Dr. Cuervo’s team reported in Nature Communications that, for the first time, they had isolated lysosomes from the brains of Alzheimer’s disease patients and observed that reduction in the number of LAMP2 receptors causes loss of CMA in humans, just as it does in animal models of Alzheimer’s.)

The researchers tested CA in two different mouse models of Alzheimer’s disease. In both disease mouse models, oral doses of CA administered over 4 to 6 months led to improvements in memory, depression, and anxiety that made the treated animals resemble or closely resemble healthy, control mice. Walking ability significantly improved in the animal model in which it was a problem. And in brain neurons of both animal models, the drug significantly reduced levels of tau protein and protein clumps compared with untreated animals.

“Importantly, animals in both models were already showing symptoms of disease, and their neurons were clogged with toxic proteins before the drugs were administered,” said Dr. Cuervo. “This means that the drug may help preserve neuron function even in the later stages of disease. We were also very excited that the drug significantly reduced gliosis — the inflammation and scarring of cells surrounding brain neurons. Gliosis is associated with toxic proteins and is known to play a major role in perpetuating and worsening neurodegenerative diseases.”

Treatment with CA did not appear to harm other organs even when given daily for extended periods of time. The drug was designed by Evripidis Gavathiotis, Ph.D.,, professor of biochemistry and of medicine and a co-leader of the study.

Drs. Cuervo and Gavathiotis have teamed up with Life Biosciences of Boston, Mass., to found Selphagy Therapeutics, which is currently developing CA and related compounds for treating Alzheimer’s and other neurodegenerative diseases.

The study is titled, “Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.” The study’s other co-leader and first author is Mathieu Bourdenx, Ph.D., a postdoctoral fellow in Dr. Cuervo’s lab and also a junior researcher at the Institute of Neurodegenerative Diseases, University of Bordeaux, France. Additional Einstein authors include: Adrián Martín-Segura, Aurora Scrivo, Susmita Kaushik, Ph.D., Inmaculada Tasset, Ph.D., Antonio Diaz and Yves R. Juste.

People Can Taste Flavor With Smell Receptors, Not Just Taste Ones

According to the latest research, the flavor of food is also a result of cell receptors associated with smelling things.

Scientists from the Monell Center report that functional olfactory receptors, the sensors that detect odors in the nose, are also present in human taste cells found on the tongue. The findings suggest that interactions between the senses of smell and taste, the primary components of food flavor, may begin on the tongue and not in the brain, as previously thought.

“Our research may help explain how odor molecules modulate taste perception,” said study senior author Mehmet Hakan Ozdener, MD, PhD, MPH, a cell biologist at Monell. “This may lead to the development of odor-based taste modifiers that can help combat the excess salt, sugar, and fat intake associated with diet-related diseases such as obesity and diabetes.”

While many people equate flavor with taste, the distinctive flavor of most foods and drinks comes more from smell than it does from taste. Taste, which detects sweet, salty, sour, bitter, and umami (savory) molecules on the tongue, evolved as a gatekeeper to evaluate the nutrient value and potential toxicity of what we put in our mouths. Smell provides detailed information about the quality of food flavor, for example, is that banana, licorice, or cherry? The brain combines input from taste, smell, and other senses to create the multi-modal sensation of flavor.

Until now, taste and smell were considered to be independent sensory systems that did not interact until their respective information reached the brain. Ozdener was prompted to challenge this belief when his 12-year-old son asked him if snakes extend their tongues so they can smell.

In the study, published online ahead of print in Chemical Senses, Ozdener and colleagues used methods developed at Monell to maintain living human taste cells in culture. Using genetic and biochemical methods to probe the taste cell cultures, the researchers found that the human taste cells contain many key molecules known to be present in olfactory receptors.

They next used a method known as calcium imaging to show that the cultured taste cells respond to odor molecules in a manner similar to olfactory receptor cells.

Together, the findings provide the first demonstration of functional olfactory receptors in human taste cells, suggesting that olfactory receptors may play a role in the taste system by interacting with taste receptor cells on the tongue. Supporting this possibility, other experiments by the Monell scientists demonstrated that a single taste cell can contain both taste and olfactory receptors.

“The presence of olfactory receptors and taste receptors in the same cell will provide us with exciting opportunities to study interactions between odor and taste stimuli on the tongue,” said Ozdener.

In addition to providing insight into the nature and mechanisms of smell and taste interactions, the findings also may provide a tool to increase understanding of how the olfactory system detects odors. Scientists still do not know what molecules activate the vast majority of the 400 different types of functional human olfactory receptors.

Health Benefits of ASMR Found in First Study of Its Kind

ASMR provides calming and stimulating sensation with no downsides currently known. It’s worth noting that the phenomenon hasn’t been researched much yet though — there may be more positives or negatives discovered in the future. There’s still an amazing amount that isn’t scientifically known about various aspects of the human mind.

Autonomous Sensory Meridian Response (ASMR) — the relaxing ‘brain tingles’ experienced by some people in response to specific triggers, such as whispering, tapping and slow hand movements — may have benefits for both mental and physical health, according to new research.

Hard Evidence that Meditation and Certain Breathing Exercises Can Sharpen the Mind

The mind can also become out of shape if it isn’t exercised regularly, similar to the body. Meditation may be worth looking at more in a world where it takes considerable mental strength to not give into a lot of technological distraction.

It has long been claimed by Yogis and Buddhists that meditation and ancient breath-focused practices, such as pranayama, strengthen our ability to focus on tasks. A new study by researchers at Trinity College Dublin explains for the first time the neurophysiological link between breathing and attention.

Breath-focused meditation and yogic breathing practices have numerous known cognitive benefits, including increased ability to focus, decreased mind wandering, improved arousal levels, more positive emotions, decreased emotional reactivity, along with many others. To date, however, no direct neurophysiological link between respiration and cognition has been suggested.

The research shows for the first time that breathing — a key element of meditation and mindfulness practices — directly affects the levels of a natural chemical messenger in the brain called noradrenaline. This chemical messenger is released when we are challenged, curious, exercised, focused or emotionally aroused, and, if produced at the right levels, helps the brain grow new connections, like a brain fertiliser. The way we breathe, in other words, directly affects the chemistry of our brains in a way that can enhance our attention and improve our brain health.

The study, carried out by researchers at Trinity College Institute of Neuroscience and the Global Brain Health Institute at Trinity, found that participants who focused well while undertaking a task that demanded a lot of attention had greater synchronisation between their breathing patterns and their attention, than those who had poor focus. The authors believe that it may be possible to use breath-control practices to stabilise attention and boost brain health.

Michael Melnychuk, PhD candidate at the Trinity College Institute of Neuroscience, Trinity, and lead author of the study, explained: “Practitioners of yoga have claimed for some 2,500 years, that respiration influences the mind. In our study we looked for a neurophysiological link that could help explain these claims by measuring breathing, reaction time, and brain activity in a small area in the brainstem called the locus coeruleus, where noradrenaline is made. Noradrenaline is an all-purpose action system in the brain. When we are stressed we produce too much noradrenaline and we can’t focus. When we feel sluggish, we produce too little and again, we can’t focus. There is a sweet spot of noradrenaline in which our emotions, thinking and memory are much clearer.”

“This study has shown that as you breathe in locus coeruleus activity is increasing slightly, and as you breathe out it decreases. Put simply this means that our attention is influenced by our breath and that it rises and falls with the cycle of respiration. It is possible that by focusing on and regulating your breathing you can optimise your attention level and likewise, by focusing on your attention level, your breathing becomes more synchronised.”

The research provides deeper scientific understanding of the neurophysiological mechanisms which underlie ancient meditation practices. The findings were recently published in a paper entitled ‘Coupling of respiration and attention via the locus coeruleus: Effects of meditation and pranayama’ in the journal Psychophysiology. Further research could help with the development of non-pharmacological therapies for people with attention compromised conditions such as ADHD and traumatic brain injury and in supporting cognition in older people.

There are traditionally two types of breath-focused practices — those that emphasise focus on breathing (mindfulness), and those that require breathing to be controlled (deep breathing practices such as pranayama). In cases when a person’s attention is compromised, practices which emphasise concentration and focus, such as mindfulness, where the individual focuses on feeling the sensations of respiration but make no effort to control them, could possibly be most beneficial. In cases where a person’s level of arousal is the cause of poor attention, for example drowsiness while driving, a pounding heart during an exam, or during a panic attack, it should be possible to alter the level of arousal in the body by controlling breathing. Both of these techniques have been shown to be effective in both the short and the long term.

Ian Robertson, Co-Director of the Global Brain Health Institute at Trinity and Principal Investigator of the study added: “Yogis and Buddhist practitioners have long considered the breath an especially suitable object for meditation. It is believed that by observing the breath, and regulating it in precise ways — a practice known as pranayama — changes in arousal, attention, and emotional control that can be of great benefit to the meditator are realised. Our research finds that there is evidence to support the view that there is a strong connection between breath-centred practices and a steadiness of mind.”

“Our findings could have particular implications for research into brain ageing. Brains typically lose mass as they age, but less so in the brains of long term meditators. More ‘youthful’ brains have a reduced risk of dementia and mindfulness meditation techniques actually strengthen brain networks. Our research offers one possible reason for this — using our breath to control one of the brain’s natural chemical messengers, noradrenaline, which in the right ‘dose’ helps the brain grow new connections between cells. This study provides one more reason for everyone to boost the health of their brain using a whole range of activities ranging from aerobic exercise to mindfulness meditation.”

Prosthetic Human Memory System Implant Successful

It’s shown to boost memory, but the fact of the software-based neural implant being demonstrated seems like it’ll have significant future implications in other ways too.

Scientists at Wake Forest Baptist Medical Center and the University of Southern California (USC) have demonstrated the successful implementation of a prosthetic system that uses a person’s own memory patterns to facilitate the brain’s ability to encode and recall memory.

In the pilot study, published in today’s Journal of Neural Engineering, participants’ short-term memory performance showed a 35 to 37 percent improvement over baseline measurements.

“This is the first time scientists have been able to identify a patient’s own brain cell code or pattern for memory and, in essence, ‘write in’ that code to make existing memory work better, an important first step in potentially restoring memory loss,” said the study’s lead author Robert Hampson, Ph.D., professor of physiology/pharmacology and neurology at Wake Forest Baptist.

The study focused on improving episodic memory, which is the most common type of memory loss in people with Alzheimer’s disease, stroke and head injury. Episodic memory is information that is new and useful for a short period of time, such as where you parked your car on any given day. Reference memory is information that is held and used for a long time, such as what is learned in school.

The researchers enrolled epilepsy patients at Wake Forest Baptist who were participating in a diagnostic brain-mapping procedure that used surgically implanted electrodes placed in various parts of the brain to pinpoint the origin of the patients’ seizures. Using the team’s electronic prosthetic system based on a multi-input multi-output (MIMO) nonlinear mathematical model, the researchers influenced the firing patterns of multiple neurons in the hippocampus, a part of the brain involved in making new memories in eight of those patients.

First, they recorded the neural patterns or ‘codes’ while the study participants were performing a computerized memory task. The patients were shown a simple image, such as a color block, and after a brief delay where the screen was blanked, were then asked to identify the initial image out of four or five on the screen.

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“We showed that we could tap into a patient’s own memory content, reinforce it and feed it back to the patient,” Hampson said. “Even when a person’s memory is impaired, it is possible to identify the neural firing patterns that indicate correct memory formation and separate them from the patterns that are incorrect. We can then feed in the correct patterns to assist the patient’s brain in accurately forming new memories, not as a replacement for innate memory function, but as a boost to it.

“To date we’ve been trying to determine whether we can improve the memory skill people still have. In the future, we hope to be able to help people hold onto specific memories, such as where they live or what their grandkids look like, when their overall memory begins to fail.”