Oral treatment with an Aβ oligomer eliminating compound enhances cognition and impedes neurodegeneration in transgenic animal models Dieter Willbold1,2, Sarah Schemmert2, Elena Schartmann2, Oleksandr Brener1, Christian Zafiu2, Thomas van Groen3, Inga Kadish3, Janine Kutzsche2, Antje Willuweit4 1Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; 2Institute of Complex Systems, ICS-6: Structural Biochemistry, Forschungszentrum Jülich, Jülich, Germany; 3Department of Cell Biology, University of Alabama at Birmingham, Birmingham Alabama, USA; 4Institute of Neuroscience and Medicine, Medical Imaging Physics (INM-4), Forschungszentrum Jülich, Jülich, Germany
Several lines of evidence suggest a central role of the amyloid-β protein (Aβ) in the pathogenesis of Alzheimer's disease (AD). More than Aβ fibrils, small soluble and prion-like propagating Aβ oligomers are suspected to be the major toxic species responsible for disease development and progression. Therefore, direct and specific eradication of these Aβ oligomers is our principal objective for a disease-modifying therapy of AD. In contrast to antibodies that have been developed to target Aβ oligomers, our strategy does not rely on a functional and efficient immune system. Starting from the fully d-enantiomeric peptide D3 we carried out a lead optimization and identified the derivative compound RD2 (“rational design number 2”) with improved properties, especially in Aβ oligomer elimination efficiency. We used our newly developed Aβ-QIAD (quantitative determination of interference with Aβ aggregate size distribution) assay to quantitatively measure Aβ oligomer elimination efficiency and thus in vitro target engagement . Morris water maze and novel object recognition experiments in several transgenic mouse models were used to measure cognition enhancement after oral treatment with the compounds. SHIRPA and Rotarod tests were used to follow neurodegeneration in the TBA2.1 mouse model and its inhibition by our compounds. In two different transgenic mouse models, RD2 demonstrated significantly improved cognition in three different laboratories, even when orally applied [2, 3]. Indeed RD2 showed superior pharmacokinetic properties, such as long terminal half-life and high oral bioavailability . In an additional study with 18 months old transgenic mice with full-blown pathology, long-term oral treatment with RD2 over 3 months led to improved cognition indistinguishable from non-transgenic littermates. After completion of this treatment study, we could demonstrate very significant reduction of Aβ oligomers in the brain homogenates of treated animals in comparison to the placebo group. This is the first successful in vivo target engagement of an Aβ oligomer eliminating compound. In a third transgenic animal model that develops neurodegeneration, oral treatment with RD2 led to drastic deceleration of the neurodegenerative phenotype.
Conclusion: The Aβ oligomers eliminating compound RD2 is able to reverse cognitive deficits and to impede neurodegeneration in transgenic mice, even when orally applied.
References:  Brener et al., Sci. Rep. 5, 13222 (2015).  van Groen et al, Sci. Rep. 7, 16275 (2017).  Kutzsche et al., Molecules 22, 1693 (2017)  Leithold et al., Pharm Res. 33, 328-336 (2016)
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