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Experimental drug shows potential against Alzheimer’s disease: Removing ‘garbage’ from brain cells improves memory in mice

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Experimental drug shows potential against Alzheimer’s disease: Removing ‘garbage’ from brain cells improves memory in mice

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.

Other contributors include: Jose A. Rodriguez-Navarro (formerly at Einstein) at Hospital Universitario Ramón y Cajal, Madrid, Spain, Nadia J. Storm (formerly at Einstein) at University of Copenhagen, Denmark, Qisheng Xin (formerly at Einstein), Erica Stevenson, Nevan Krogan and Danielle L. Swaney both at University of California at San Francisco, CA, Enrique Luengo at Universidad Autonoma de Madrid, Madrid, Spain, Cristina Clement, Ph.D., and Laura Santambrogio, M.D., Ph.D., both at Weill Cornell Medicine, New York, NY, Se Joon Choi, Ph.D., Eugene V. Mosharov and David Sulzer, Ph.D., all at Columbia University Medical Center, New York, NY and Fiona Grueninger, Ph.D., and Ludovic Collin both at Roche Pharma, Switzerland.

The study was supported by the National Institutes of Health (AG054108, AG021904, AG017617, AG038072, AG031782, NS100717, NS095435), the JPB Foundation, the Rainwater Charitable Foundation, Michael J. Fox Foundation, and the Backus Foundation.

Drs. Cuervo and Gavathiotis are cofounders and scientific advisory board members of Selphagy Therapeutics Inc. now part of Life Bioscience (Boston, MA). CA compound is under the following patent: Retinoic acid receptor antagonists as chaperone-mediated autophagy modulators and uses thereof; Gavathiotis E, Cuervo AM, Xin Q, Das BC; United States patent granted US9512092; 2016 Dec 16. The remaining authors declare no competing interests.

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Mechanism found to determine which memories last

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Experimental drug shows potential against Alzheimer’s disease: Removing ‘garbage’ from brain cells improves memory in mice


Neuroscientists have established in recent decades the idea that some of each day’s experiences are converted by the brain into permanent memories during sleep the same night. Now, a new study proposes a mechanism that determines which memories are tagged as important enough to linger in the brain until sleep makes them permanent.

Led by researchers from NYU Grossman School of Medicine, the study revolves around brain cells called neurons that “fire” — or bring about swings in the balance of their positive and negative charges — to transmit electrical signals that encode memories. Large groups of neurons in a brain region called the hippocampus fire together in rhythmic cycles, creating sequences of signals within milliseconds of each other that can encode complex information.

Called “sharp wave-ripples,” these “shouts” to the rest of the brain represent the near-simultaneous firing of 15 percent of hippocampal neurons, and are named for the shape they take when their activity is captured by electrodes and recorded on a graph.

While past studies had linked ripples with memory formation during sleep, the new study, published online in the journal Science on March 28, found that daytime events followed immediately by five to 20 sharp wave-ripples are replayed more during sleep and so consolidated into permanent memories. Events followed by very few or no sharp wave-ripples failed to form lasting memories.

“Our study finds that sharp wave-ripples are the physiological mechanism used by the brain to ‘decide’ what to keep and what to discard,” said senior study author György Buzsáki, MD, PhD, the Biggs Professor of Neuroscience in the Department of Neuroscience and Physiology at NYU Langone Health.

Walk and Pause

The new study is based on a known pattern: mammals including humans experience the world for a few moments, then pause, then experience a little more, then pause again. After we pay attention to something, say the study authors, brain computation often switches into an “idle” re-assessment mode. Such momentary pauses occur throughout the day, but the longest idling periods occur during sleep.

Buzsaki and colleagues had previously established that no sharp wave-ripples occur as we actively explore sensory information or move, but only during the idle pauses before or after. The current study found that sharp wave-ripples represent the natural tagging mechanism during such pauses after waking experiences, with the tagged neuronal patterns reactivated during post-task sleep.

Importantly, sharp wave-ripples are known to be made up the firing of hippocampal “place cells” in a specific order that encodes every room we enter, and each arm of a maze entered by a mouse. For memories that are remembered, those same cells fire at high speed, as we sleep, “playing back the recorded event thousands times per night.” The process strengthens the connections between the cells involved.

For the current study, successive maze runs by study mice were tracked via electrodes by populations of hippocampal cells that constantly changed over time despite recording very similar experiences. This revealed for the first time the maze runs during which ripples occurred during waking pauses, and then were replayed during sleep.

Sharp wave-ripples were typically recorded when a mouse paused to enjoy a sugary treat after each maze run. The consumption of the reward, say the authors, prepared the brain to switch from an exploratory to an idle pattern so that sharp wave-ripples could occur.

Using dual-sided silicon probes, the research team was able to record up to 500 neurons simultaneously in the hippocampus of animals during maze runs. This in turn created a challenge because data becomes exceedingly complex the more neurons are independently recorded. To gain an intuitive understanding of the data, visualize neuronal activity, and form hypotheses, the team successfully reduced the number of dimensions in the data, in some ways like converting a three-dimensional image into a flat one, and without losing the data’s integrity.

“We worked to take the external world out of the equation, and looked at the mechanisms by which the mammalian brain innately and subconsciously tags some memories to become permanent,” said first author Wannan (Winnie) Yang, PhD, a graduate student in Buzsáki’s lab. “Why such a system evolved is still a mystery, but future research may reveal devices or therapies that can adjust sharp wave-ripples to improve memory, or even lessen recall of traumatic events.”

Along with Drs. Buzsáki and Yang, study authors from the Neuroscience Institute at NYU Langone Health were Roman Huszár and Thomas Hainmueller. Kirill Kiselev of the Center for Neural Science at New York University was also an author, as was Chen Sun of Mila, the Quebec Artificial Intelligence Institute, in Montréal. The work was supported by National Institute of Health grants R01MH122391 and U19NS107616.



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Long-period oscillations control the Sun’s differential rotation

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Experimental drug shows potential against Alzheimer’s disease: Removing ‘garbage’ from brain cells improves memory in mice


The Sun’s differential rotation pattern has puzzled scientists for decades: while the poles rotate with a period of approximately 34 days, mid-latitudes rotate faster and the equatorial region requires only approximately 24 days for a full rotation. In addition, in past years advances in helioseismology, i.e. probing the solar interior with the help of solar acoustic waves, have established that this rotational profile is nearly constant throughout the entire convection zone. This layer of the Sun stretches from a depth of approximately 200,000 kilometers to the visible solar surface and is home to violent upheavals of hot plasma which play a crucial role in driving solar magnetism and activity.

While theoreticaThe interior of the Sun does not rotate at the same rate at all latitudes. The physical origin of this differential rotation is not fully understood. A team of scientists at the Max Planck Institute for Solar System Research (MPS) in Germany has made a ground-breaking discovery. As the team reports today in the journal Science Advances, the long-period solar oscillations discovered by MPS scientists in 2021 play a crucial role in controlling the Sun’s rotational pattern. The long-period oscillations are analogous to the baroclinically unstable waves in Earth’s atmosphere that shape the weather. In the Sun, these oscillations carry heat from the slightly hotter poles to the slightly cooler equator. To obtain their new results, the scientists interpreted observations from NASA’s Solar Dynamics Observatory using cutting-edge numerical simulations of the solar interior. They found that the difference in temperature between the poles and the equator is about seven degrees.

l models have long postulated a slight temperature difference between solar poles and equator to maintain the Sun’s rotational pattern, it has proven notoriously difficult to measure. After all, observations have to “look through” the background of the Sun’s deep interior which measures up to million degrees in temperature. However, as the researchers from MPS show, it is now possible to determine the temperature difference from the observations of the long-period oscillations of the Sun.

In their analysis of observational data obtained by the Helioseismic and Magnetic Imager (HMI) onboard NASA’s Solar Dynamics Observatory from 2017 to 2021, the scientists turned to global solar oscillations with long periods that can be discerned as swirling motions at the solar surface. Scientists from MPS reported their discovery of these inertial oscillations three years ago. Among these observed modes, the high-latitude modes with velocities of up to 70 km per hour, proved to be especially influential.

To study the nonlinear nature of these high-latitude oscillations, a set of three-dimensional numerical simulations was conducted. In their simulations, the high-latitude oscillations carry heat from the solar poles to the equator, which limits the temperature difference between the Sun’s poles and the equator to less than seven degrees. “This very small temperature difference between the poles and the equator controls the angular momentum balance in the Sun and thus is an important feedback mechanism for the Sun’s global dynamics” says MPS Director Prof. Dr. Laurent Gizon.

In their simulations, the researchers for the first time described the crucial processes in a fully three-dimensional model. Former endeavors had been limited to two-dimensional approaches that assumed the symmetry about the Sun’s rotation axis. “Matching the nonlinear simulations to the observations allowed us to understand the physics of the long-period oscillations and their role in controlling the Sun’s differential rotation,” says MPS postdoc and the lead author of the study, Dr. Yuto Bekki.

The solar high-latitude oscillations are driven by a temperature gradient in a similar way to extratropical cyclones on the Earth. The physics is similar, though the details are different: “In the Sun, the solar pole is about seven degrees hotter than equator and this is enough to drive flows of about 70 kilometers per hour over a large fraction of the Sun. The process is somewhat similar to the driving of cyclones,” says MPS scientist Dr. Robert Cameron.

Probing the physics of the Sun’s deep interior is difficult. This study is important as it shows that the long-period oscillations of the Sun are not only useful probes of the solar interior, but that they play an active role in the way the Sun works. Future work, which will be carried out in the context of the ERC Synergy Grant WHOLESUN and the DFG Collaborative Research Center 1456 Mathematics of Experiments, will be aimed at better understanding the role of these oscillations and their diagnostic potential.



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Artificial reef designed by MIT engineers could protect marine life, reduce storm damage

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Experimental drug shows potential against Alzheimer’s disease: Removing ‘garbage’ from brain cells improves memory in mice


The beautiful, gnarled, nooked-and-crannied reefs that surround tropical islands serve as a marine refuge and natural buffer against stormy seas. But as the effects of climate change bleach and break down coral reefs around the world, and extreme weather events become more common, coastal communities are left increasingly vulnerable to frequent flooding and erosion.

An MIT team is now hoping to fortify coastlines with “architected” reefs — sustainable, offshore structures engineered to mimic the wave-buffering effects of natural reefs while also providing pockets for fish and other marine life.

The team’s reef design centers on a cylindrical structure surrounded by four rudder-like slats. The engineers found that when this structure stands up against a wave, it efficiently breaks the wave into turbulent jets that ultimately dissipate most of the wave’s total energy. The team has calculated that the new design could reduce as much wave energy as existing artificial reefs, using 10 times less material.

The researchers plan to fabricate each cylindrical structure from sustainable cement, which they would mold in a pattern of “voxels” that could be automatically assembled, and would provide pockets for fish to explore and other marine life to settle in. The cylinders could be connected to form a long, semipermeable wall, which the engineers could erect along a coastline, about half a mile from shore. Based on the team’s initial experiments with lab-scale prototypes, the architected reef could reduce the energy of incoming waves by more than 95 percent.

“This would be like a long wave-breaker,” says Michael Triantafyllou, the Henry L. and Grace Doherty Professor in Ocean Science and Engineering in the Department of Mechanical Engineering. “If waves are 6 meters high coming toward this reef structure, they would be ultimately less than a meter high on the other side. So, this kills the impact of the waves, which could prevent erosion and flooding.”

Details of the architected reef design are reported today in a study appearing in the open-access journal PNAS Nexus. Triantafyllou’s MIT co-authors are Edvard Ronglan SM ’23; graduate students Alfonso Parra Rubio, Jose del Auila Ferrandis, and Erik Strand; research scientists Patricia Maria Stathatou and Carolina Bastidas; and Professor Neil Gershenfeld, director of the Center for Bits and Atoms; along with Alexis Oliveira Da Silva at the Polytechnic Institute of Paris, Dixia Fan of Westlake University, and Jeffrey Gair Jr. of Scinetics, Inc.

Leveraging turbulence

Some regions have already erected artificial reefs to protect their coastlines from encroaching storms. These structures are typically sunken ships, retired oil and gas platforms, and even assembled configurations of concrete, metal, tires, and stones. However, there’s variability in the types of artificial reefs that are currently in place, and no standard for engineering such structures. What’s more, the designs that are deployed tend to have a low wave dissipation per unit volume of material used. That is, it takes a huge amount of material to break enough wave energy to adequately protect coastal communities.

The MIT team instead looked for ways to engineer an artificial reef that would efficiently dissipate wave energy with less material, while also providing a refuge for fish living along any vulnerable coast.

“Remember, natural coral reefs are only found in tropical waters,” says Triantafyllou, who is director of the MIT Sea Grant. “We cannot have these reefs, for instance, in Massachusetts. But architected reefs don’t depend on temperature, so they can be placed in any water, to protect more coastal areas.”

The new effort is the result of a collaboration between researchers in MIT Sea Grant, who developed the reef structure’s hydrodynamic design, and researchers at the Center for Bits and Atoms (CBA), who worked to make the structure modular and easy to fabricate on location. The team’s architected reef design grew out of two seemingly unrelated problems. CBA researchers were developing ultralight cellular structures for the aerospace industry, while Sea Grant researchers were assessing the performance of blowout preventers in offshore oil structures — cylindrical valves that are used to seal off oil and gas wells and prevent them from leaking.

The team’s tests showed that the structure’s cylindrical arrangement generated a high amount of drag. In other words, the structure appeared to be especially efficient in dissipating high-force flows of oil and gas. They wondered: Could the same arrangement dissipate another type of flow, in ocean waves?

The researchers began to play with the general structure in simulations of water flow, tweaking its dimensions and adding certain elements to see whether and how waves changed as they crashed against each simulated design. This iterative process ultimately landed on an optimized geometry: a vertical cylinder flanked by four long slats, each attached to the cylinder in a way that leaves space for water to flow through the resulting structure. They found this setup essentially breaks up any incoming wave energy, causing parts of the wave-induced flow to spiral to the sides rather than crashing ahead.

“We’re leveraging this turbulence and these powerful jets to ultimately dissipate wave energy,” Ferrandis says.

Standing up to storms

Once the researchers identified an optimal wave-dissipating structure, they fabricated a laboratory-scale version of an architected reef made from a series of the cylindrical structures, which they 3D-printed from plastic. Each test cylinder measured about 1 foot wide and 4 feet tall. They assembled a number of cylinders, each spaced about a foot apart, to form a fence-like structure, which they then lowered into a wave tank at MIT. They then generated waves of various heights and measured them before and after passing through the architected reef.

“We saw the waves reduce substantially, as the reef destroyed their energy,” Triantafyllou says.

The team has also looked into making the structures more porous, and friendly to fish. They found that, rather than making each structure from a solid slab of plastic, they could use a more affordable and sustainable type of cement.

“We’ve worked with biologists to test the cement we intend to use, and it’s benign to fish, and ready to go,” he adds.

They identified an ideal pattern of “voxels,” or microstructures, that cement could be molded into, in order to fabricate the reefs while creating pockets in which fish could live. This voxel geometry resembles individual egg cartons, stacked end to end, and appears to not affect the structure’s overall wave-dissipating power.

“These voxels still maintain a big drag while allowing fish to move inside,” Ferrandis says.

The team is currently fabricating cement voxel structures and assembling them into a lab-scale architected reef, which they will test under various wave conditions. They envision that the voxel design could be modular, and scalable to any desired size, and easy to transport and install in various offshore locations. “Now we’re simulating actual sea patterns, and testing how these models will perform when we eventually have to deploy them,” says Anjali Sinha, a graduate student at MIT who recently joined the group.

Going forward, the team hopes to work with beach towns in Massachusetts to test the structures on a pilot scale.

“These test structures would not be small,” Triantafyllou emphasizes. “They would be about a mile long, and about 5 meters tall, and would cost something like 6 million dollars per mile. So it’s not cheap. But it could prevent billions of dollars in storm damage. And with climate change, protecting the coasts will become a big issue.”

This work was funded, in part, by the U.S. Defense Advanced Research Projects Agency.



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