A highly toxic beta-amyloid - a protein that exists in the brainsof Alzheimer's disease victims - has been found to greatly increase the toxicity of othermore common and less toxic beta-amyloids, serving as a possible"trigger" for the advent and development of Alzheimer's,researchers at the University of Virginia and German biotechcompany Probiodrug have discovered. The finding, reported in the journal Nature , could lead to more effective treatments for Alzheimer's. Already,Probiodrug AG, based in Halle, Germany has completed phase 1clinical trials in Europe with a small molecule that inhibits anenzyme, glutaminyl cyclase, that catalyzes the formation of thishypertoxic version of beta-amyloid. "This form of beta-amyloid, called pyroglutamylated (or pyroglu)beta-amyloid, is a real bad guy in Alzheimer's disease," saidprincipal investigator George Bloom, a U.Va. professor of biologyand cell biology in the College of Arts & Sciences and School ofMedicine, who is collaborating on the study with scientists atProbiodrug. |
"We've confirmed that it converts more abundantbeta-amyloids into a form that is up to 100 times more toxic,making this a very dangerous killer of brain cells and anattractive target for drug therapy." Bloom said the process is similar to various prion diseases, suchas mad cow disease or chronic wasting disease, where a toxicprotein can "infect" normal proteins that spread through the brainand 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 canfurther contaminate something that's already bad into somethingmuch worse - it's the trigger," Bloom said. Just as importantly,the hypertoxic mixtures that are seeded by pyroglu beta-amyloidexist as small aggregates, called oligomers, rather than as muchlarger fibers found in the amyloid plaques that are a signaturefeature of the Alzheimer's brain.
And the trigger fires a "bullet," as Bloom puts it. The bullet is aprotein called tau that is stimulated by beta-amyloid to form toxic"tangles" in the brain that play a major role in the onset anddevelopment of Alzheimer's. Using mice bred to have no tau genes,the researchers found that without the interaction of toxicbeta-amyloids with tau, the Alzheimer's cascade cannot begin. Thepathway by which pyroglu beta-amyloid induces the tau-dependentdeath of neurons is now the target of further investigation tounderstand this important step in the early development ofAlzheimer's disease "There are two matters of practical importance in our discovery,"Bloom said. "One, is the new insights we have as to how Alzheimer'smight actually progress - the mechanisms which are important tounderstand if we are to try to prevent it from happening; andsecond, it provides a lead into how to design drugs that mightprevent this kind of beta-amyloid from building up in the firstplace." Said study co-author Hans-Ulrich Demuth, a biochemist and chiefscientific officer at Probiodrug, "This publication further addssignificant evidence to our hypothesis about the critical rolepyroglu beta-amyloid plays in the initiation of Alzheimer'sDisease.
For the first time we have found a clear link in therelationship between pyroglu beta-amyloid, oligomer formation andtau protein in neuronal toxicity." Bloom and his collaborators are now looking for other proteins thatare needed for pyroglu beta-amyloid to become toxic. Any suchproteins they discover are potential targets for the earlydiagnosis and/or treatment of Alzheimer's disease. Additional References Citations.
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