Tag: Hans-Ulrich Demuth

Innovation Radar: Probiodrug’s Nature Paper Receives Broad Coverage

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.

As an example, further reports appeared in Der Standard (Austria) and La Stampa (Italy).

Company News: Probiodrug AG, Collaborators Explain Interplay of Key Suspects in Alzheimer’s Disease

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.

Read more

Company News: Neurodegeneration in Alzheimer’s Disease: The crucial role of QC

Probiodrug provides further insights into the onset of AD in The Journal of Neuroscience

Probiodrug AG (Probiodrug), a biotech company developing novel products for the treatment of neurodegenerative and inflammatory disorders, today announced the publication of data providing key insights into the onset and development of Alzheimer’s disease (AD) in the Journal of Neuroscience (http://redir.ec/jneurosci).

AD is characterized by deposition of amyloid-β (Aβ) plaques in the brain. However, quantitative relationship between plaque deposition and severity of cognitive decline in the affected individuals is still elusive. Often, elderly people carry a large amyloid burden without any signs of cognitive impairments, and many animal models of AD also develop the characteristic hallmarks, such as plaques, but do not demonstrate the cognitive defects and loss of neurons typical of the human disease.

Several years ago, Probiodrug developed the hypothesis that the missing link between Aβ load and prevalence of AD is a certain modification of Aβ, in which the Aβ molecule carries a pyroglutamate residue (pGlu) at its N-terminus. This pGlu-Aβ is neurotoxic and develops a strong tendency to aggregate and to seed aggregation of further pGlu-Aβ as well as unmodified Aβ. The modification of glutamic acid to a pGlu-residue is catalyzed by the so-called QC enzyme (glutaminyl cyclase).

In this week’s The Journal of Neuroscience* Probiodrug researchers (and their collaborators from Friedrich Alexander University, Erlangen, the German Center of Neurodegenerative Diseases, Magdeburg, the Leibniz Institute for Neurobiology, Magdeburg, the Paul Flechsig Institute for Brain Research, Leipzig, and the University of Tennessee, Knoxville/ USA) now describe the generation and characterization of a novel animal model that solely expresses N-truncated human Aβ, which in turn is modified by QC to pGlu-Aβ. As a result, these animals which express the toxic species 1000fold less than other models do with Aβ not only have the typical pathological changes, but also neuronal loss and cognitive impairments.

”We now have animal models that represent the full spectrum of pathological and behavioral changes in AD without overexpressing the Aβ peptides. In addition, we could once again clearly demonstrate that the activity of QC enzymes is starting the chain of events that ultimately leads to the debilitating disease, which already affects millions of people world-wide. The results in this study also demonstrate that lowering the QC-dependent formation of pGlu-Aβ reduces the amount of neurotoxic aggregations, and further strengthens the hypothesis that inhibition of QC is a promising new treatment strategy for AD” commented Hans Ulrich Demuth, CSO of Probiodrug.