Right target, but missing the bulls-eye for Alzheimer's

January 24, 2013

(Medical Xpress)—Alzheimer's disease is the most common cause of late-life dementia. The disorder is thought to be caused by a protein known as amyloid-beta, or Abeta, which clumps together in the brain, forming plaques that are thought to destroy neurons. This destruction starts early, too, and can presage clinical signs of the disease by up to 20 years.

For decades now, researchers have been trying, with limited success, to develop drugs that prevent this clumping. Such drugs require a "target"—a structure they can bind to, thereby preventing the toxic actions of Abeta.

Now, a new study out of UCLA suggests that while researchers may have the right target in Abeta, they may be missing the bull's-eye. Reporting in the Jan. 23 issue of the , UCLA neurology professor David Teplow and colleagues focused on a particular segment of a toxic form of Abeta and discovered a unique -like structure that facilitates clumping.

"Every 68 seconds, someone in this country is diagnosed with 's," said Teplow, the study's senior author and principal investigator of the 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 once it begins. Most of the drugs that have been developed have either failed or only provide modest improvement of the symptoms. So finding a better for these potential therapeutics is critical."

The Abeta is composed of a sequence of , much like "a pearl necklace composed of 20 different combinations of different colors of pearl," Teplow said. One form of Abeta, Abeta40, has 40 amino acids, while a second form, Abeta42, has two extra amino acids at one end.

Abeta42 has long been thought to be the toxic form of Abeta, but until now, no one has understood how the simple addition of two amino acids made it so much more toxic then Abeta40.

In his lab, Teplow and his colleagues used computer simulations in which they looked at the structure of the Abeta proteins in a virtual world. The researchers first created a virtual Abeta peptide that only contained the last 12 amino acids of the entire 42–amino-acid-long Abeta42 protein. Then, said Teplow, "we just let the molecule move around in a virtual world, letting the laws of physics determine how each atom of the peptide was attracted to or repulsed by other atoms."

By taking thousands of snapshots of the various molecular structures the peptides created, the researchers determined which structures formed more frequently than others. From those, they then physically created mutant Abeta peptides using chemical synthesis.

"We studied these mutant peptides and found that the structure that made Abeta42 Abeta42 was a hairpin-like turn at the very end of the peptide of the whole Abeta protein," Teplow said.

The hairpin turn structure was not previously known in the detail revealed by the researchers, "so we feel our experiments were novel," he said. "Our lab is the first to show that it is this specific turn that accounts for the special ability of Abeta42 to aggregate into that we think kills neurons. Abeta40, the Abeta protein with two less amino acids at the end of the protein, did not do the same thing."

Hopefully, the work of the Teplow laboratory presents what may the most relevant target yet for the development of drugs to fight Alzheimer's disease, the researchers said.

Explore further: Researchers identify how a gene linked to both Alzheimer's disease and type 2 diabetes works

Related Stories

Researchers identify how a gene linked to both Alzheimer's disease and type 2 diabetes works

July 18, 2011
Researchers at Mount Sinai School of Medicine have identified how a gene for a protein that can cause Type 2 diabetes, also possibly kills nerve cells in the brain, thereby contributing to Alzheimer's disease.

Natural Alzheimer's weapon suggests better treatment

June 20, 2011
Scientists have shown a molecular chaperone is working like a waste management company to collect and detoxify high levels of toxic amyloid beta peptide found in Alzheimer's disease.

Poor recycling of BACE1 enzyme could promote Alzheimer's disease

November 21, 2011
Sluggish recycling of a protein-slicing enzyme could promote Alzheimer's disease, according to a study published online on November 21 in The Journal of Cell Biology.

Noncoding RNA may promote Alzheimer's disease

May 30, 2011
Researchers pinpoint a small RNA that spurs cells to manufacture a particular splice variant of a key neuronal protein, potentially promoting Alzheimer's disease (AD) or other types of neurodegeneration. The study appears ...

Recommended for you

Lifestyle changes to stave off Alzheimer's? Hints, no proof

July 20, 2017
There are no proven ways to stave off Alzheimer's, but a new report raises the prospect that avoiding nine key risks starting in childhood just might delay or even prevent about a third of dementia cases around the world.

Blood test identifies key Alzheimer's marker

July 19, 2017
A new study led by researchers at Washington University School of Medicine in St. Louis suggests that measures of amyloid beta in the blood have the potential to help identify people with altered levels of amyloid in their ...

Steering an enzyme's 'scissors' shows potential for stopping Alzheimer's disease

July 19, 2017
The old real estate adage about "location, location, location" might also apply to the biochemical genesis of Alzheimer's disease, according to new research from the University of British Columbia.

Brain scans may change care for some people with memory loss

July 19, 2017
Does it really take an expensive brain scan to diagnose Alzheimer's? Not everybody needs one but new research suggests that for a surprising number of patients whose memory problems are hard to pin down, PET scans may lead ...

Can poor sleep boost odds for Alzheimer's?

July 18, 2017
(HealthDay)— Breathing problems during sleep may signal an increased risk for Alzheimer's disease, a trio of studies suggests.

Hearing is believing: Speech may be a clue to mental decline

July 17, 2017
Your speech may, um, help reveal if you're uh ... developing thinking problems. More pauses, filler words and other verbal changes might be an early sign of mental decline, which can lead to Alzheimer's disease, a study suggests.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.