Food for Thought: Key to Stopping Alzheimer’s Disease

In Germany, newpapers are widely reporting about a recent paper by a team of researchers led by  Thomas Bayer from Ernst-August University Goettingen, Germany, in which the team reports about an approach able to halt the progress of Alzheimer’s disease in mice.

For a long time, researchers have tried to stop Alzheimer’s disease (AD) by either dissolving the plaques found in the brains of AD patients or by trying to get rid of the so-called Abeta peptide that is believed to aggregate to plaques. However, none of these approaches has been successful so far.

A couple of years ago, researchers from the biotech company Probiodrug AG (Halle, Germany) found that the major culprit for the detrimental aggregation of peptides to plaques is not Abeta as such, but a variation carrying a pyroglutamate residue. This pyroglutamated Abeta peptide (pGlu-Abeta), they found, is generated by a hitherto unknown reaction catalyzed by the brain enzyme glutaminyl cyclase (QC). pGlu-formation leads to stabilization of the peptide and protection against cleavage. Moreover, Probiodrug has been able to demonstrate that pGlu-Abeta peptides show increased neurotoxicity, a prolonged half-life and an increased tendency for aggregation. They also form the seeds of the typical plaques observed in the brain of AD patients.

While Probiodrug is developing small molecule inhibitors of the QC enzyme to halt the disease, Thomas Bayer (who is a member of Probiodrug’s Scientific Advisory Board) and his team generated a monoclonal antibody against pGlu-Abeta. Passive immunization of transgenic mice models of AD  with this monoclonal antibody significantly reduced overall Abeta plaque load and levels of pGlu-Abeta, and also normalized behavioral deficit in the mice.

Later this month during the Neuroscience 2010 conference, Probiodrug will demonstrate that increasing pGlu-Abeta potentiates the behavioral deficits observed with transgenic AD mouse models significantly, and will also presented data showing that inhibitors of QC can reduce the level of pyroglutamated beta-amyloid species and alleviate the observed behavioral changes.

While the approach presented by Thomas Bayer will take a few years to reach the clinic, Probiodrug’s first small molecule QC inhibitor already has reached the regulatory phase.