This week’s Nature publication by researchers of Probiodrug AG and the University of Virginia has received broad coverage in the international media. In Germany and Austria, it made major news in TV (ARD, MDR, ORF) and radio stations (dlf, MDR, dradio), while in the US Rudy Tanzi, neurogeneticist of Harvard Medical School and an advisor on the Alzheimer problem to US-President Barack Obama, was quoted in ScienceNews as saying: “This opens up a whole new view of the disease.”
Alzheimer researcher Thomas Bayer, Professor of Molecular Psychiatry at the University of Goettingen added in MDR INFO that the publication was “a very important contribution”, demonstrating that very small amounts of pGlu Abeta were able to drag normal Abeta peptides along into the deadly cascade and that tau protein was essential for the toxic function.
Nature paper demonstrates that toxicity in AD is induced by pyroglutamate Abeta and is tau protein dependent
Pyroglutamate Ab (“pyroglu Ab”) a predominant, highly toxic fraction of Aβ found in the brains of Alzheimer’s disease patients, triggers the formation of toxic oligomers exhibiting prion-like behavior and initiating neurotoxicity via a tau protein-dependent pathway, thereby explaining the crucial role of such modified Aβ in the onset and spread of neuronal toxicity in Alzheimer’s Disease.
HALLE/SAALE, Germany, May 2, 2012 – Probiodrug AG (Probiodrug), a biotech company developing products for the treatment of neurodegenerative and inflammatory diseases with a particular focus on Alzheimer’s disease (AD), today announced its scientists and academics collaborators published seminal findings on the role of pyroglu Aβ in AD pathology in the May 2, 2012 online edition of the journal Nature (DOI: 10.1038/nature11060). The new findings add to the growing body of evidence that pyroglu Aβ plays a crucial role in the initiation of AD. In addition, the research results further elucidate the mechanism by which pyroglu Aβ triggers neuronal toxicity.
The data published today suggest that pyroglu Aβ co-aggregates with “normal” Ab peptides to form low molecular weight oligomers (LMOs), which are structurally distinct and far more toxic to cultured neurons than oligomers derived from normal Aβ. Moreover, the presence of the neuronal protein tau is essential for toxicity mediated by LMOs that contain pyroglu Aβ. The results have been substantiated in transgenic mice designed to express increased levels of pyroglu Aβ. In these animals, the pyroglu Aβ-mediated neuronal loss and gliosis was prevented, if tau expression was shut down. The study is supplemented by results published in the Journal of Neurochemistry. Here the Probiodrug researchers reveal, that the aggregation propensity is caused by the hydrophobic nature of pyroglu Aβ.
The scientists also were able to demonstrate that the cytotoxicity is propagated by a prion-like templating mechanism of Ab misfolding initiated by pyroglu Ab: even after strong dilution to a solution containing only 0.000625% pyroglu Ab, the mix after 24h developed enough toxicity to kill 50% of neurons treated with it.
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.