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Mol Neurobiol. 2019 Mar;56(3):2211-2223. doi: 10.1007/s12035-018-1209-3. Epub 2018 Jul 12.

Aβ Oligomer Elimination Restores Cognition in Transgenic Alzheimer's Mice with Full-blown Pathology.

Author information

1
Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425, Jülich, Germany.
2
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich Heine University Düsseldorf, Leibniz Centre for Diabetes Research, Düsseldorf, Germany.
3
German Center for Diabetes Research (DZD), Partner Düsseldorf, Germany.
4
Institute of Neuroscience and Medicine, Medical Imaging Physics (INM-4), Forschungszentrum Jülich, 52425, Jülich, Germany.
5
Clinic for Nuclear Medicine, RWTH Aachen University, Aachen, Germany.
6
Department of Neurology, Faculty of Medicine, JARA, RWTH Aachen University, Aachen, Germany.
7
Institute of Neuroscience and Medicine, Medical Imaging Physics (INM-4), Forschungszentrum Jülich, 52425, Jülich, Germany. a.willuweit@fz-juelich.de.
8
Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425, Jülich, Germany. d.willbold@fz-juelich.de.
9
Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. d.willbold@fz-juelich.de.

Abstract

Oligomers of the amyloid-β (Aβ) protein are suspected to be responsible for the development and progression of Alzheimer's disease. Thus, the development of compounds that are able to eliminate already formed toxic Aβ oligomers is very desirable. Here, we describe the in vivo efficacy of the compound RD2, which was developed to directly and specifically eliminate toxic Aβ oligomers. In a truly therapeutic, rather than a preventive study, oral treatment with RD2 was able to reverse cognitive deficits and significantly reduce Aβ pathology in old-aged transgenic Alzheimer's Disease mice with full-blown pathology and behavioral deficits. For the first time, we demonstrate the in vivo target engagement of RD2 by showing a significant reduction of Aβ oligomers in the brains of RD2-treated mice compared to placebo-treated mice. The correlation of Aβ elimination in vivo and the reversal of cognitive deficits in old-aged transgenic mice support the hypothesis that Aβ oligomers are relevant not only for disease development and progression, but also offer a promising target for the causal treatment of Alzheimer's disease.

KEYWORDS:

Alzheimer’s disease therapy; Amyloid-β oligomer elimination; D-enantiomeric peptides; Target engagement; Transgenic mice

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