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Biochemists discover new insights into what may go awry in brains of people with Alzheimer’s

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Photo of two researchers in lab.

Research by UCLA professor Steven Clarke and former graduate student Rebeccah Warmack, as well as UCLA colleagues, reveals new information about the brain’s biochemistry.

More than three decades of research on Alzheimer’s disease have not produced any major treatment advances for those with the disorder, according to a UCLA expert who has studied the biochemistry of the brain and Alzheimer’s for nearly 30 years. “Nothing has worked,” said Steven Clarke, a distinguished professor of chemistry and biochemistry. “We’re ready for new ideas.” Now, Clarke and UCLA colleagues have reported new insights that may lead to progress in fighting the devastating disease.

Scientists have known for years that amyloid fibrils — harmful, elongated, water-tight rope-like structures — form in the brains of people with Alzheimer’s, and likely hold important clues to the disease. UCLA Professor David Eisenberg and an international team of chemists and molecular biologists reported in the journal Nature in 2005 that amyloid fibrils contain proteins that interlock like the teeth of a zipper. The researchers also reported their hypothesis that this dry molecular zipper is in the fibrils that form in Alzheimer’s disease, as well as in Parkinson’s disease and two dozen other degenerative diseases. Their hypothesis has been supported by recent studies.

Alzheimer’s disease, the most common cause of dementia among older adults, is an irreversible, progressive brain disorder that kills brain cells, gradually destroys memory and eventually affects thinking, behavior and the ability to carry out the daily tasks of life. More than 5.5 million Americans, most of whom are over 65, are thought to have dementia caused by Alzheimer’s.

The UCLA team reports in the journal Nature Communications that the small protein beta amyloid, also known as a peptide, that plays an important role in Alzheimer’s has a normal version that may be less harmful than previously thought and an age-damaged version that is more harmful.

Rebeccah Warmack, who was a UCLA graduate student at the time of the study and is its lead author, discovered that a specific version of age-modified beta amyloid contains a second molecular zipper not previously known to exist. Proteins live in water, but all the water gets pushed out as the fibril is sealed and zipped up. Warmack worked closely with UCLA graduate students David Boyer, Chih-Te Zee and Logan Richards; as well as senior research scientists Michael Sawaya and Duilio Cascio.

What goes wrong with beta amyloid, whose most common forms have 40 or 42 amino acids that are connected like a string of beads on a necklace?

The researchers report that with age, the 23rd amino acid can spontaneously form a kink, similar to one in a garden hose. This kinked form is known as isoAsp23. The normal version does not create the stronger second molecular zipper, but the kinked form does.

“Now we know a second water-free zipper can form, and is extremely difficult to pry apart,” Warmack said. “We don’t know how to break the zipper.”

The normal form of beta amyloid has six water molecules that prevent the formation of a tight zipper, but the kink ejects these water molecules, allowing the zipper to form.

When one of its amino acids forms a kink, beta amyloid creates a harmful molecular zipper, shown here in green. Photo credit: Rebeccah Warmack/UCLA

When one of its amino acids forms a kink, beta amyloid creates a harmful molecular zipper, shown here in green.
“Rebeccah has shown this kink leads to faster growth of the fibrils that have been linked to Alzheimer’s disease,” said Clarke, who has conducted research on biochemistry of the brain and Alzheimer’s disease since 1990. “This second molecular zipper is double trouble. Once it’s zipped, it’s zipped, and once the formation of fibrils starts, it looks like you can’t stop it. The kinked form initiates a dangerous cascade of events that we believe can result in Alzheimer’s disease.”

Why does beta amyloid’s 23rd amino acid sometimes form this dangerous kink?

Clarke thinks the kinks in this amino acid form throughout our lives, but we have a protein repair enzyme that fixes them.

“As we get older, maybe the repair enzyme misses the repair once or twice,” he said. “The repair enzyme might be 99.9% effective, but over 60 years or more, the kinks eventually build up. If not repaired or if degraded in time, the kink can spread to virtually every neuron and can do tremendous damage.”

“The good news is that knowing what the problem is, we can think about ways to solve it,” he added. “This kinked amino acid is where we want to look.”

The research offers clues to pharmaceutical companies, which could develop ways to prevent formation of the kink or get the repair enzyme to work better; or by designing a cap that would prevent fibrils from growing.

Clarke said beta amyloid and a much larger protein tau — with more than 750 amino acids — make a devastating one-two punch that forms fibrils and spreads them to many neurons throughout the brain. All humans have both beta amyloid and tau. Researchers say it appears that beta amyloid produces fibrils that can lead to tau aggregates, which can spread the toxicity to other brain cells. However, exactly how beta amyloid and tau work together to kill neurons is not yet known.

In this study, Warmack produced crystals, both the normal and kinked types, in 15 of beta amyloid’s amino acids. She used a modified type of cryo-electron microscopy to analyze the crystals. Cryo-electron microscopy, whose development won its creators the 2017 Nobel Prize in chemistry, enables scientists to see large biomolecules in extraordinary detail. Professor Tamir Gonen pioneered the modified microscopy, called microcrystal electron diffraction, which enables scientists to study biomolecules of any size.

Eisenberg is UCLA’s Paul D. Boyer Professor of Molecular Biology and a Howard Hughes Medical Institute investigator. Other researchers are co-author Gonen, a professor of biological chemistry and physiology at the UCLA David Geffen School of Medicine and a Howard Hughes Medical Institute investigator; and Jose Rodriguez, assistant professor of chemistry and biochemistry who holds the Howard Reiss Career Development Chair.

The research was funded by the National Science Foundation, National Institutes of Health, Howard Hughes Medical Institute, and the UCLA Longevity Center’s Elizabeth and Thomas Plott Chair in Gerontology, which Clarke held for five years.

This article originally appeared in the UCLA Newsroom.

New simulations suggest that carbon (C) routinely bonded with iron (Fe), silicon (Si) and oxygen (O) deep within the magma ocean that covered Earth when it was young.

New insights about carbon and ice could clarify inner workings of Earth, other planets

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New simulations suggest that carbon (C) routinely bonded with iron (Fe), silicon (Si) and oxygen (O) deep within the magma ocean that covered Earth when it was young.

New simulations suggest that carbon (C) routinely bonded with iron (Fe), silicon (Si) and oxygen (O) deep within the magma ocean that covered Earth when it was young.

 

Most people behave differently when under extreme pressure. Carbon and ice are no different.

Two new studies show how these key planetary ingredients take on exotic forms that could help researchers better understand the composition of Earth’s core as well as the cores of planets across the galaxy. Craig Manning, a UCLA professor of geology and geochemistry, is a co-senior author of one of the papers, which was published today in the journal Nature, and senior author of the other, which was published in Nature Communications in February.

The Nature Communications paper revealed that high pressure deep inside the young Earth may have driven vast stores of carbon into the planet’s core while also setting the stage for diamonds to form. In the Nature report, researchers found that water ice undergoes a complex crystalline metamorphosis as the pressure slowly ratchets up.

Scientists have long understood that the amount of carbon sequestered in present-day Earth’s rocks, oceans and atmosphere is always in flux because the planet shuffles the element around in a vast cycle that helps regulate climate. But researchers don’t know whether the Earth locked away even more carbon deep in its interior during its formative years — information that could reveal a little more about how our planet and others like it are built.

To pursue an answer to that question, Manning and colleagues calculated how carbon might have interacted with other atoms under conditions similar to those that prevailed roughly 4.5 billion years ago, when much of Earth was still molten. Using supercomputers, the team created simulations to explore what would happen to carbon at temperatures above 3,000 degrees Celsius (more than 5,400 degrees Fahrenheit) and at pressures more than 100,000 times of those on Earth’s surface today.

The experiment revealed that under those conditions, carbon tends to link up with iron, which implies that there might be considerable quantities of carbon sealed in Earth’s iron core today. Researchers had already suspected that in the young planet’s magma ocean, iron atoms hooked up with one another and then dropped to the planet’s center. But the new research suggests that this molten iron rain may have also dragged carbon down with it. Until now, researchers weren’t even sure whether carbon exists down there.

The team also found that as the pressure ramps up, carbon increasingly bonds with itself, forming long chains of carbon atoms with oxygen atoms sticking out.

“These complex chains are a form of carbon bonding that we really hadn’t anticipated at these conditions,” Manning said.

Such molecules could be a precursor to diamonds, which consist of many carbon atoms linked together.

Solving an icy enigma

The machinations of carbon under pressure provide clues as to how Earth-like planets are built. Frozen planets and moons in other solar systems, however, may also have to contend with water ice. In a separate paper, Manning and another team of scientists looked at how the molecular structure of extremely cold ice changes when put under intense pressure.

Under everyday conditions, water ice is made up of molecules laid out in honeycomb-like mosaics of hexagons. But when ice is exposed to crushing pressure or very low temperature — in labs or possibly deep inside remote worlds — the molecules can assume a bewildering variety of patterns.

One of those patterns, known as amorphous ice, is an enigma. In amorphous ice, the water molecules eschew rigid crystalline order and take on a free-form arrangement. Manning and colleagues set out to try and understand how amorphous ice forms.

First, they chilled normal ice to about 170 degrees below zero Celsius (about 274 degrees below zero Fahrenheit). Then, they locked the ice in the jaws of a high-tech vice grip inside a cryogenic vacuum chamber. Finally, over the span of several hours, they slowly stepped up the pressure in the chamber to about 15,000 times atmospheric pressure. They stopped raising the pressure periodically to fire neutrons through the ice so that they could see the arrangement of the water molecules.

Surprisingly to the researchers, the amorphous ice never formed. Instead, the molecules went through a series of previously known crystalline arrangements.

However, when the researchers conducted the same experiment but raised the pressure much more rapidly — this time in just 30 minutes — amorphous ice formed as expected. The results suggest that time is the secret ingredient: When pressure increases slowly, tiny seeds of crystalline ice have time to form and take over the sample. Otherwise, those seeds never get a chance to grow.

The findings, published May 23 in the journal Nature, could be useful to researchers who study worlds orbiting other suns and are curious about what conditions might be like deep inside frozen planets.

“It’s entirely likely that there are planets dominated by ice in other solar systems that could obtain these pressures and temperatures with ease,” Manning said. “We have to have this right if we’re going to have a baseline for understanding the interiors of cold worlds that may not be like Earth.”

Both papers were funded in part by the Deep Carbon Observatory, a 10-year program started in 2009 to investigate the quantities, movements, forms and origins of deep carbon inside Earth. The Nature Communications paper was also funded by the European Research Council and was co-authored by researchers at the Ecole Normale Supérieure de Lyon in France, one of whom — Natalia Solomatova — completed her undergraduate studies at UCLA. The Nature paper was co-authored by UCLA geologist Adam Makhluf and researchers from Oak Ridge National Laboratory and the National Research Council of Canada.

This article originally appeared on the UCLA Newsroom.

 

Best in snow: New scientific device creates electricity from snowfall

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UCLA researchers and colleagues have designed a new device that creates electricity from falling snow. The first of its kind, this device is inexpensive, small, thin and flexible like a sheet of plastic.

“The device can work in remote areas because it provides its own power and does not need batteries,” said senior author Richard Kaner, who holds UCLA’s Dr. Myung Ki Hong Endowed Chair in Materials Innovation. “It’s a very clever device — a weather station that can tell you how much snow is falling, the direction the snow is falling, and the direction and speed of the wind.”

The researchers call it a snow-based triboelectric nanogenerator, or snow TENG. A triboelectric nanogenerator, which generates charge through static electricity, produces energy from the exchange of electrons.

Findings about the device are published in the journal Nano Energy.

Maher El-Kady and Richard Kaner

Maher El-Kady and Richard Kaner

“Static electricity occurs from the interaction of one material that captures electrons and another that gives up electrons,” said Kaner, who is also a distinguished professor of chemistry and biochemistry, and of materials science and engineering, and a member of the California NanoSystems Institute at UCLA. “You separate the charges and create electricity out of essentially nothing.”

Snow is positively charged and gives up electrons. Silicone — a synthetic rubber-like material that is composed of silicon atoms and oxygen atoms, combined with carbon, hydrogen and other elements — is negatively charged. When falling snow contacts the surface of silicone, that produces a charge that the device captures, creating electricity.

“Snow is already charged, so we thought, why not bring another material with the opposite charge and extract the charge to create electricity?” said co-author Maher El-Kady, a UCLA assistant researcher of chemistry and biochemistry.

“While snow likes to give up electrons, the performance of the device depends on the efficiency of the other material at extracting these electrons,” he added. “After testing a large number of materials including aluminum foils and Teflon, we found that silicone produces more charge than any other material.”

About 30 percent of the Earth’s surface is covered by snow each winter, during which time solar panels often fail to operate, El-Kady noted. The accumulation of snow reduces the amount of sunlight that reaches the solar array, limiting the panels’ power output and rendering them less effective. The new device could be integrated into solar panels to provide a continuous power supply when it snows, he said.

Hiking shoe with device attached

Hiking shoe with device attached

The device can be used for monitoring winter sports, such as skiing, to more precisely assess and improve an athlete’s performance when running, walking or jumping, Kaner said. It also has the potential for identifying the main movement patterns used in cross-country skiing, which cannot be detected with a smart watch.

It could usher in a new generation of self-powered wearable devices for tracking athletes and their performances.

It can also send signals, indicating whether a person is moving. It can tell when a person is walking, running, jumping or marching.

The research team used 3-D printing to design the device, which has a layer of silicone and an electrode to capture the charge. The team believes the device could be produced at low cost given “the ease of fabrication and the availability of silicone,” Kaner said. Silicone is widely used in industry, in products such as lubricants, electrical wire insulation and biomedical implants, and it now has the potential for energy harvesting.

Co-authors include Abdelsalam Ahmed, who conducted the research while completing his doctoral studies at the University of Toronto; Islam Hassan and Ravi Selvaganapathy of Canada’s McMaster University; and James Rusling of the University of Connecticut and his research team.

Kaner’s research was funded by Nanotech Energy, a company spun off from his research (Kaner is chair of its scientific advisory board and El-Kady is chief technology officer); and Kaner’s Dr. Myung Ki Hong Endowed Chair in Materials Innovation.

Kaner’s laboratory has produced numerous devices, including a membrane that separates oil from water and cleans up the debris left by oil fracking. Fracking is a technique to extract gas and oil from shale rock.

Kaner, El-Kady and colleagues designed a device in 2017 that can use solar energy to inexpensively and efficiently create and store energy, which could be used to power electronic devices and to create hydrogen fuel for eco-friendly cars. This year, they published research on their design of the first fire-retardant, self-extinguishing motion sensor and power generator, which could be embedded in shoes or clothing worn by firefighters and others who work in harsh environments.

Kaner is among the world’s most influential and highly cited scientific researchers. He was selected as the recipient of the American Institute of Chemists 2019 Chemical Pioneer Award, which honors chemists and chemical engineers who have made outstanding contributions that advance the science of chemistry or greatly impact the chemical profession.

UCLA-led center receives $9.75 million to improve rechargeable batteries

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With the funding, the new UCLA-led Synthetic Control Across Length-scales for Advancing Rechargeables center, or SCALAR, will help accelerate research on new types of chemistry and materials for rechargeable batteries.

UCLA’s Neil Garg wins country’s leading teaching award and its $250,000 prize

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The Cherry Award honors outstanding professors who are extraordinary, inspiring teachers with a positive, long-lasting effect on students and a record of distinguished scholarship.

Hydrogen cars for the masses one step closer to reality, thanks to UCLA invention

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UCLA researchers have designed a device that can use solar energy to inexpensively and efficiently create and store energy, which could be used to power electronic devices, and to create hydrogen fuel for eco-friendly cars.

$2 million gift from alumnus establishes UCLA faculty chairs in chemistry and biochemistry

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The gift will create the Dr. Myung Ki Hong Endowed Chair in Polymer Science and the Dr. Myung Ki Hong Endowed Chair in Materials Innovation.

J. Fraser Stoddart wins 2016 Nobel Prize in chemistry

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J. Fraser Stoddart, who was a professor of chemistry and biochemistry at UCLA from 1997 to 2008 and is currently the Board of Trustees Professor of Chemistry at Northwestern University, has been awarded the 2016 Nobel Prize in chemistry, the Nobel committee announced this morning.

Three UCLA professors named 2016 Guggenheim Fellows

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A trio of UCLA faculty members are among a distinguished group of 178 of scholars, artists and scientists from the U.S. and Canada to receive 2016 Guggenheim Fellowships.

In memoriam: Professor emeritus Howard Reiss

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Elected to the National Academy of Sciences in 1977, Reiss was an accomplished physical chemist and theorist who worked in a variety of fields, including including solid state, statistical mechanics, nucleation and colloid phenomena, polymers, electrochemistry, thermodynamics and device physics.