Probiodrug AG, Collaborators Explain Interplay of Key Suspects in Alzheimer's Disease
The data published today suggest that pyroglu Aß co-aggregates with “normal” Aß peptides to form low molecular weight oligomers (LMOs), which are structurally distinct and far more toxic to cultured neurons than oligomers derived from normal Aß. Moreover, the presence of the neuronal protein tau is essential for toxicity mediated by LMOs that contain pyroglu Aß. The results have been substantiated in transgenic mice designed to express increased levels of pyroglu Aß. In these animals, the pyroglu Aß 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 Aß.
The scientists also were able to demonstrate that the cytotoxicity is propagated by a prion-like templating mechanism of Aß misfolding initiated by pyroglu Aß: even after strong dilution to a solution containing only 0.000625% pyroglu Aß, 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 Aß 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 Aß containing or propagated low-molecular weight oligomers remain stable for days - in contrast to the short-lived oligomers not formed by the pyroglu Aß initiated mechanism. The new data for the first time demonstrate a relationship between pyroglu Aß 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 Aß 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.”
About Probiodrug AG
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.