Attenuation of Alzheimer’s disease-like pathology by inhibition of glutaminyl cyclase catalyzed pyroglutamate Aβ formation in transgenic animals
Halle/Saale, November 15, 2008 — Probiodrug AG (Probiodrug), a developer of small molecule inhibitors for the treatment of neurodegenerative and inflammatory diseases, announced today that the company will present an update on its human glutaminyl cyclase inhibition program for the treatment of Alzheimer’s disease (AD) at the Society for Neuroscience Meeting 2008, Nov. 15-19, 2008, Washington, DC.
At the conference, Probiodrug will present the company’s progress in validation of human glutam(in)yl cyclase (QC) enzymes as a target for treatment of Alzheimer’s disease and neuroinflammation.
Probiodrug`s studies provide strong evidence for a glutaminyl cyclase (QC, EC 184.108.40.206) catalyzed cyclization of N-terminal glutamine or glutamic acid residues of peptides. The reactions are either crucial for maturation of pro-inflammatory cytokines like MCP-1, or for formation of pGlu-modified amyloid peptides in neurodegenerative amyloidoses like AD and Familial Danish Dementia, respectively. Pyroglutamate (pGlu)-modified Aβ peptides are major constituents of plaques in AD. Formation of pGlu at the N-terminus of Aβ decreases its solubility, which, in turn, speeds up Aβ aggregate formation. Moreover, pGlu confers resistance against cleavage by most aminopeptidases and neprilysin. Interestingly, the appearance of pGlu-Aβ apparently coincides with an upregulation of QC in AD.
To evaluate the role of pGlu-Aβ in mouse models with AD-like pathology, a QC-inhibitor was applied orally to the familial AD mouse models Tg2576 and TASD-41 for different durations under prophylactic and therapeutic conditions. In the prophylactic studies, a dose-dependent effect of the QC-inhibitor on solubilized pGlu-Aβ as well as Aβ(x-42) was observed. Apparently, the reduction of pGlu-Aβ results in diminished aggregation of other, more abundant Aβ species, supporting the hypothesis of pGlu-Aβ acting as a nidus for aggregation of Aβ. The treatment is accompanied by improvements of spatial and contextual fear memory as determined by Morris Water Maze and conditioned fear paradigms. In therapeutic studies, a dose-dependent reduction of pGlu-Aβ was observed which was also accompanied by a dose-dependent decrease of amyloid plaques.
Summarizing, the catalytic feature of QC to provoke the N-terminal pGlu-formation from glutamine and glutamic acid with significant proficiency, suggests a crucial role of the enzyme for the formation of N-terminally pyroglutamated amyloid peptides. The accumulation of these degradation-resistant peptides with a high propensity for aggregation influences the amyloid-plaque formation /stabilization and likely influences the toxicity of Aβ, as also suggested by Probiodrug`s novel transgenic mouse models. Thus, inhibition of glutaminyl cyclase represents a novel approach to interfere with amyloid-driven neurodegeneration in disorders with enhanced production of pGlu-modified peptides.
Probiodrug is a biopharmaceutical company specialized on the development of innovative small molecule drugs for the treatment of neuronal, inflammatory, and autoimmune diseases. In these areas, Probiodrug is focusing on innovative targets with the prospect of first and best in class therapeutics.
Dr Konrad Glund, CEO
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Tel.: +49 345 55599-00
Fax: +49 345 55599-01
Dr Ludger Weß
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Germany Tel.: +49 40 88 16 59 64
Fax: +49 40 88 16 59 65