UCLA research could help lead to design of drugs that slow neurodegeneration
Alzheimer's disease destroys brain cells in part by promoting the formation of insoluble clumps that contain a protein called tau. Not only are these "tau aggregates" toxic for the cells that harbor them, but they also invade and destroy neighboring brain cells, or neurons, which speeds the cognitive decline associated with the Alzheimer's.
For those reasons, Alzheimer's researchers have been intensely interested in therapies aimed at either preventing tau aggregation or blocking its spread.
Now, researchers at the UCLA School of Nursing and the department of neurology at the David Geffen School of Medicine at UCLA have reported a promising drug strategy that blocks tau transmission. The study was published online in the journal Biochemical and Biophysical Research Communications.
Using cultured cells, mouse models and protein structural analysis, the researchers found that a small molecule called cambinol blocks the transfer of tau aggregates from cell to cell. The study could help lay the groundwork for therapies to treat Alzheimer's or other dementias associated with the accumulation of tau.
"Over 200 molecules have been tested as disease-modifying Alzheimer's therapy in clinical trials, and none has yet attained the holy grail," said Varghese John, a UCLA associate professor of neurology and the study's senior author. "Our paper describes a novel approach to slow Alzheimer's progression by showing it is possible to inhibit propagation of pathologic forms of tau."
John is a member of the UCLA Easton Center for Alzheimer's Disease Research and leads the Drug Discovery and Translational lab.
In healthy people, tau proteins are benign building blocks of a neuron's framework, or cytoskeleton. But in Alzheimer's disease, tau proteins fall away from the cytoskeleton, become abnormally modified, and then form insoluble "neurofibrillary tangles" that destroy cells. To make matters worse, dying cells encase tau aggregates in lipid vesicles called exosomes, which then bud off and "seed" neighboring tissues, keeping the destructive cycle going.
The researchers conducted several experiments that suggest that cambinol can subvert the "transfer" step by blocking an enzyme called nSMase2, which is essential for catalyzing production of the exosome carriers. In one, the scientists used "donor cells" that harbored tau aggregates derived from postmortem human Alzheimer's specimens and mixed them with tau-free recipient cells.
Without cambinol, the aggregates spread from donors to recipients, mirroring what happens in the brains of people with Alzheimer's. But when treated with cambinol, recipient cells remained tau-free when grown side by side with tau-positive donors, presumably because the drug disabled nSMase2 activity blocking release of the tau-carrying exosomes.
The researchers also observed decreased nSMase2 catalytic activity in the brains of mice that were given cambinol orally. John said the seemingly routine experiment was an essential first step. "Getting molecules into the brain is a big hurdle, because most drugs don't penetrate the blood-brain barrier," he said, referring to the membranes that surround the central nervous system and keep drugs out of it. "Now we know we can treat animals with cambinol to determine its effect on Alzheimer's pathology and progression."
The paper is the first to report on a model of how cambinol switches off nSMase2 catalytic activity at the atomic level, and it provides critical knowledge for medicinal chemists like John to begin designing new drugs based on cambinol that are more potent and efficacious than the molecule itself. That work is already being done in collaboration with Neil Garg, a UCLA professor of chemistry and biochemistry. If the approach is successful in animals, it could be tested in clinical trials.
"Understanding pathways is the first step to new drug targets," said Karen Gylys, a UCLA professor of nursing and a co-author of the study. "With cambinol in hand, we have a useful tool for understanding cellular pathways that enable the spread of tau pathology."
UCLA's Tina Bilousova is the study's lead author. Other authors, all of UCLA, are Chris Elias, Emily Miyoshi, Mohammad-Parvez Alam, Chunni Zhu, Jesus Campagna, Kanagasabai Vadivel and Barbara Jagodzinska.
The study was supported by grants from the National Institute of Aging and the UCLA Department of Neurology.
Mechanism Discovered to Activate the Immune System against Bacteria and Regulate the Microbiome
13.02.2019 | Universitätsklinikum Tübingen
For the first time, an international team of scientists based in Regensburg, Germany, has recorded the orbitals of single molecules in different charge states in a novel type of microscopy. The research findings are published under the title “Mapping orbital changes upon electron transfer with tunneling microscopy on insulators” in the prestigious journal “Nature”.
The building blocks of matter surrounding us are atoms and molecules. The properties of that matter, however, are often not set by these building blocks...
Scientists at the University of Konstanz identify fierce competition between the human immune system and bacterial pathogens
Cell biologists from the University of Konstanz shed light on a recent evolutionary process in the human immune system and publish their findings in the...
Laser physicists have taken snapshots of carbon molecules C₆₀ showing how they transform in intense infrared light
When carbon molecules C₆₀ are exposed to an intense infrared light, they change their ball-like structure to a more elongated version. This has now been...
The so-called Abelian sandpile model has been studied by scientists for more than 30 years to better understand a physical phenomenon called self-organized...
Physicists from the University of Basel have developed a new method to examine the elasticity and binding properties of DNA molecules on a surface at extremely low temperatures. With a combination of cryo-force spectroscopy and computer simulations, they were able to show that DNA molecules behave like a chain of small coil springs. The researchers reported their findings in Nature Communications.
DNA is not only a popular research topic because it contains the blueprint for life – it can also be used to produce tiny components for technical applications.
11.02.2019 | Event News
30.01.2019 | Event News
16.01.2019 | Event News
15.02.2019 | Physics and Astronomy
15.02.2019 | Physics and Astronomy
15.02.2019 | Life Sciences