– Nature paper demonstrates that toxicity in AD is induced by pyroglutamate Abeta and is tau protein dependent –
Pyroglutamate Aβ (“pyroglu Aβ”) 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. 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” Aβ 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 (online April 2012). 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 Aβ misfolding initiated by pyroglu Aβ: even after strong dilution to a solution containing only 0.000625% pyroglu Aβ, the mix after 24h developed enough toxicity to kill 50% of neurons treated with it.
“This publication delivers significant evidence to our hypothesis that pyroglu Aβ plays a critical role in the initiation of AD,” said Prof. Dr. Hans-Ulrich Demuth, CSO of Probiodrug. “It was also extremely surprising to us, that the pyroglu Aβ containing or propagated low-molecular weight oligomers remain stable for days – in contrast to the short-lived oligomers not formed by the pyroglu Aβ initiated mechanism. The new data for the first time demonstrate a relationship between pyroglu Aβ oligomer formation and tau protein in the development of neuronal toxicity.”
Konrad Glund, CEO of Probiodrug, adds: “It is a great step forward in our understanding of the disease mechanism. In addition, it supports Probiodrug’s therapeutic approach to block Glutaminyl Cyclase, the enzyme responsible for pyroglu Aβ formation, with small molecule inhibitors as a treatment for AD. PQ912, the lead candidate, has just completed phase I trials successfully; the company is now preparing first patient studies.”
Probiodrug is a biopharmaceutical company dedicated to the discovery and development of small molecule drugs against novel molecular targets for the treatment of neuronal- and inflammatory diseases. The Company has a dominant position in the area of glutaminyl cyclase inhibition. Glutaminyl cyclase, a novel enzyme target discovered and patented by Probiodrug, has a crucial role in the pathogenesis of Alzheimer’s disease (AD) as well as various peripheral inflammatory diseases.
Probiodrug is backed by institutions such as BB Biotech, Edmond de Rothschild Investment Partners, Goodvent/IBG, HBM, TVM, Life Sciences Partners, Biogen Idec Ventures, CFH Group and private investors.
Probiodrug’s core capabilities are based on its long-standing expertise in the elucidation of the structure and function of enzymes which play a central role in the maturation of hormones. The Company has pioneered the field of dipeptidyl peptidase 4 (DP4)-inhibition for the treatment of type 2 diabetes. Compounds and technology patents of its DP4 program in diabetes were licensed to various pharmaceutical companies. In 2004, all metabolic assets were sold to (OSI) Pharmaceuticals Ltd. The first drug based on Probiodrug`s technologies reached the market in late 2006. Proceeds of the various transactions have been reinvested to fund the novel approach for the treatment of AD and inflammatory diseases.
The Company was founded in 1997 by Prof Dr Hans-Ulrich Demuth and Dr Konrad Glund. Probiodrug has raised EUR 71 mio for its QC program. For more information, please visit www.probiodrug.de.
Prof. Dr. Hans-Ulrich Demuth
+49 345 55599-05
Dr. Ludger Wess or Ines Buth
+49 40 88165964