Amyloid-β Gets Toxic Helping Hand

Amyloid-β, the peptide that misfolds and then forms plaques in the brains of Alzhei­mer’s patients, likely misfolds with help from a less prevalent, modified version of itself, according to a report in Nature (DOI: 10.1038/nature11060). Scientists have suspected that forms of amyloid-β modified with an amino-terminal pyroglutamate trigger unmodified amyloid to misfold, but they haven’t been sure of the mechanism for this interaction. On the basis of in vitro studies in neurons, George S. Bloom of the University of Virginia; Hans-Ulrich Demuth of Probiodrug, a biopharma firm in Germany; and coworkers propose that pyro­glutamylated amyloid-β (pE-Aβ), which readily folds into a toxic form, acts as a template for amyloid-β, helping to convert it into a more dangerous oligomeric form. By itself, a 42-residue version of amyloid-β had almost no effect on neurons to which it was added for 12 hours. But an oligomerized mixture of 95% amyloid-β and 5% 39-residue pE-Aβ killed about 60% of neurons over the same period. The team also showed that pE-Aβ needs tau protein, another macromolecule implicated in Alzheimer’s, to kill nerve cells. In mice engineered to lack tau and to overproduce pE-Aβ, neurons remained intact for at least three months.