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According to a UCLA expert, who has been studying biochemistry of the brain and Alzheimer's disease for nearly 30 years, more than three decades of Alzheimer's disease research have has not led to major therapeutic progress for people with "Nothing has worked," said Steven Clarke, Distinguished Professor of Chemistry and Biochemistry. "We are ready for new ideas." Now, Clarke and his colleagues at UCLA have brought forward new ideas to advance the fight against this devastating disease.
Scientists have known for years that amyloid fibrils – harmful, elongated and tight rope-like structures – form in the brains of people with Alzheimer's disease and are probably important clues to the disease. Professor David Eisenberg of UCLA and an international team of chemists and molecular biologists have been reported in the journal Nature in 2005, amyloid fibrils contain proteins that nest together like the teeth of a zipper. The researchers also reported their hypothesis that this dry molecular zipper is found 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 in the elderly, is an irreversible progressive brain disorder that kills brain cells, progressively destroys memory, and eventually affects thinking, behavior and ability to lead to the daily tasks of life. More than 5.5 million Americans, most of whom are over the age of 65, would have dementia caused by Alzheimer's disease.
The reports of the UCLA team in the newspaper Nature Communications that the small beta-amyloid protein, also called peptide, which plays an important role in Alzheimer's disease, has a normal version that may be less harmful than previously thought and a damaged version by the Age that is more harmful.
Rebeccah Warmack, a graduate student at UCLA at the time of the study and its lead author, discovered that a specific version of age-modified beta amyloid contained a second molecular zipper whose existence did not exist. The proteins live in the water, but all the water is expelled when the fibril is sealed and closed. Warmack worked closely with David Boyer, Chih-Te Zee and Logan Richards, graduate students at UCLA; as well as principal investigators Michael Sawaya and Duilio Cascio.
What's wrong with beta-amyloid, whose most common forms have 40 or 42 amino acids that are connected as a string of pearls on a necklace?
The researchers report that with age, the 23rd amino acid can spontaneously form a fold, similar to that of a watering hose. This curved shape is known as isoAsp23. The normal version does not create the second stronger molecular zipper, but the folded form does.
"We now know that a second zipper without water can form and that it is extremely difficult to separate it," Warmack said. "We do not know how to break the zipper."
The normal form of beta-amyloid contains six water molecules that prevent the formation of a watertight zipper, but kink ejects these molecules of water, allowing the closure to form.
"Rebeccah has shown that this sprain is accelerating the growth of fibrils related to Alzheimer's disease," said Clarke, who has been conducting research on brain biochemistry and Alzheimer's disease since 1990. "This second Molecular zipper is a double problem.Once it is compressed, and once fibril formation has begun, it seems that you can not stop it.The curved shape initiates a dangerous waterfall. events that we believe can lead to Alzheimer's disease. "
Why does the 23rd amino acid beta-amyloid sometimes form this dangerous bend?
Clarke thinks that the problems of this form of amino acid throughout our lives, but we have a protein repair enzyme that corrects them.
"As you get older, the repair enzyme may be missing the repair once or twice," he said. "The enzyme repair could be effective at 99.9%, but after 60 years or more, the folds accumulate .If they are not repaired or if they degrade over time, they can spread to virtually any neuron and cause considerable damage. "
"The good news is that, knowing the problem, we can think of ways to solve it," he added. "This folded amino acid is where we want to look."
The research offers clues to pharmaceutical companies, who could develop ways to prevent kink formation or improve the effectiveness of the repair enzyme; or by designing a cap preventing the growth of fibrils.
Clarke said that beta-amyloid and a much larger protein, containing more than 750 amino acids, produced a devastating double blow that formed fibrils and diffused them into many neurons in the brain. All humans have both beta-amyloid and tau. The researchers say that it appears that beta-amyloid produces fibrils that can lead to the formation of tau aggregates, likely to spread toxicity to other brain cells. However, it is still unclear how beta-amyloid and beta-amyloid proteins work together to kill neurons.
In this study, Warmack produced crystals, normal and bent, in amino acids of beta-amyloid. She used a modified type of cryo-electronic microscopy to analyze the crystals. Cryogenic electron microscopy, whose development earned its creators the Nobel Prize in Chemistry 2017, allows scientists to see large biomolecules with an extraordinary level of detail. Professor Tamir Gonen has been the pioneer of modified microscopy, called electron microcrystal diffraction, which allows scientists to study biomolecules of any size.
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