Health & Medicine - Posted by Fariss Samarrai-Virginia on Thursday, May 3, 2012 11:17 - 0 Comments
Alzheimer’s protein sparks toxic ‘tangle’
U. VIRGINIA (US) — A highly toxic protein in the brains of people with Alzheimer’s disease may serve as a “trigger” for the condition’s progress.
The protein, a highly toxic beta-amyloid, greatly increases the toxicity of other more common and less toxic beta-amyloids, possibly setting off the development of Alzheimer’s, say researchers at the University of Virginia and the German biotech company Probiodrug AG.
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The findings, reported in the May 2 online edition of the journal Nature, could lead to more effective treatments for Alzheimer’s, which is currently thought to affect 5.4 million Americans.
Researchers at Probiodrug have completed phase 1 clinical trials in Europe with a small molecule that inhibits an enzyme, glutaminyl cyclase, that catalyzes the formation of this hypertoxic version of beta-amyloid.
“This form of beta-amyloid, called pyroglutamylated (or pyroglu) beta-amyloid, is a real bad guy in Alzheimer’s disease,” says principal investigator George Bloom, a University of Virginia professor of biology and cell biology.
“We’ve confirmed that it converts more abundant beta-amyloids into a form that is up to 100 times more toxic, making this a very dangerous killer of brain cells and an attractive target for drug therapy.”
Bloom says the process is similar to various prion diseases, such as mad cow disease or chronic wasting disease, where a toxic protein can “infect” normal proteins that spread through the brain and ultimately destroy it.
In the case of Alzheimer’s, severe dementia occurs over the course of years prior to death.
“You might think of this pyroglu beta-amyloid as a seed that can further contaminate something that’s already bad into something much worse—it’s the trigger,” Bloom says.
Just as importantly, the hypertoxic mixtures that are seeded by pyroglu beta-amyloid exist as small aggregates, called oligomers, rather than as much larger fibers found in the amyloid plaques that are a signature feature of the Alzheimer’s brain.
And the trigger fires a “bullet,” as Bloom puts it. The bullet is a protein called tau that is stimulated by beta-amyloid to form toxic “tangles” in the brain that play a major role in the onset and development of Alzheimer’s.
Using mice bred to have no tau genes, the researchers found that without the interaction of toxic beta-amyloids with tau, the Alzheimer’s cascade cannot begin. The pathway by which pyroglu beta-amyloid induces the tau-dependent death of neurons is now the target of further investigation to understand this important step in the early development of Alzheimer’s disease.
“There are two matters of practical importance in our discovery,” Bloom says. “One, is the new insights we have as to how Alzheimer’s might actually progress—the mechanisms which are important to understand if we are to try to prevent it from happening; and second, it provides a lead into how to design drugs that might prevent this kind of beta-amyloid from building up in the first place.”
“This publication further adds significant evidence to our hypothesis about the critical role pyroglu beta-amyloid plays in the initiation of Alzheimer’s disease. For the first time we have found a clear link in the relationship between pyroglu beta-amyloid, oligomer formation and tau protein in neuronal toxicity,” says study co-author Hans-Ulrich Demuth, a biochemist and chief scientific officer at Probiodrug.
Bloom and his collaborators are now looking for other proteins that are needed for pyroglu beta-amyloid to become toxic. Any such proteins they discover are potential targets for the early diagnosis and/or treatment of Alzheimer’s disease.
More news from the University of Virginia: www.virginia.edu/uvatoday