Hairpin for Alzheimer's
Alzheimer's disease: The target is right, but the bullets don't hit the bullseye
LifeSciencesToday based on UCLA materials: Right target, but missing the bulls-eye for Alzheimer'sAlzheimer's disease is the most common cause of dementia in older people.
It is believed that this disease is caused by the beta-amyloid protein accumulating in the brain, clusters of which form so-called beta-amyloid plaques that destroy neurons. The disease begins to develop very early – decades before the first clinical signs appear.
Scientists have been trying to develop drugs that prevent beta-amyloid clustering for many decades. Such drugs should have a target structure, interaction with which prevents the toxic effect of beta–amyloid.
A study conducted by scientists at the University of California at Los Angeles (University of California, Los Angeles, UCLA) shows that, although the target for drugs - beta–amyloid protein - is chosen correctly, the "bullets" do not hit the bullseye. UCLA neurology professor David Teplow and his colleagues focused their attention on a certain fragment of the toxic form of beta-amyloid and discovered a unique hairpin structure that facilitates its adhesion. An article about the results of the study was published in the Journal of Molecular Biology (C-Terminal Turn Stability Determines Assembly Differences between A-beta40 and A-beta42).
"Every 68 seconds, someone in this country is diagnosed with Alzheimer's disease," says Professor Teplou, chief researcher at the US National Institutes of Health (NIH)-sponsored Alzheimer's Disease Research Center at UCLA. "Alzheimer's disease is the only one of the top 10 causes of death in America that cannot be prevented, cured or even slowed down if it has started. Most of the drugs developed have either failed completely or provide temporary relief of symptoms. Therefore, finding a more efficient molecular pathway for potential drugs is vital."
Beta-amyloid protein consists of a sequence of amino acids, "very similar to a pearl necklace of 20 different combinations of multi–colored pearls," explains Professor Teplou. One form of beta-amyloid, A-beta40, consists of 40 amino acids, while the other form, A-beta42, differs from A-beta40 by two additional amino acids at one end. A-beta42 has long been considered a toxic form of beta-amyloid, but until now no one could explain how the simple addition of two amino acids makes it so much more toxic than A-beta40.
Oligomerization of beta-amyloid peptide is a fundamental event in the development of Alzheimer's disease. The C-terminal bend (beta-hairpin structure) makes A-beta42 particularly toxic and pathogenic. This structure can be an extremely important therapeutic target. The yellow dotted line shows hydrogen bonds. The atoms C, N, O and S are shown in green, blue, red and yellow, respectively. The red arrows indicate the C-terminal hairpin bend.
(Fig. Journal of Molecular Biology)
Professor Teplou and his colleagues decided to study the structure of beta-amyloid proteins using computer modeling. First, scientists created a virtual beta-amyloid peptide containing only the last 12 amino acids of the 42-amino acid A-beta42. Then, says the professor, "we simply allowed the molecule to rotate in virtual space, allowing the laws of physics to determine how each atom of the peptide is attracted to other atoms or repelled from them."
Having obtained thousands of images of various molecular structures formed by peptides, the researchers determined which of them are formed more often than others. Then, on their basis, using chemical synthesis, they physically created mutant beta-amyloid peptides.
"We studied these mutant peptides and found that the structure determining the pathogenic properties of A-beta42 is a hairpin bend at the very end of this peptide," says Professor Teplou. "Our laboratory was the first to show that this particular bend is responsible for the specific ability of A-beta42 to clump together into clumps, which we believe kill neurons. Protein A-beta40 – shorter by two amino acids –does not do this."
The structure of the hairpin bend was not previously known in such details. Scientists hope that they have managed to find what may be the most relevant target of drugs to combat Alzheimer's disease.
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