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

Molecular Neurobiology
Sarah SchemmertDieter Willbold

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.

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Citations

Sep 5, 2019·Acta Neuropathologica Communications·Charlotte GaryMarc Dhenain
Jun 19, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dieter Willbold, Janine Kutzsche
Dec 18, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Olujide O OlubiyiBirgit Strodel
Jul 3, 2020·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Adam B EdwardsBruno P Meloni
Mar 27, 2020·Alzheimer's & Dementia : Translational Research & Clinical Interventions·Janine KutzscheDieter Willbold
Feb 22, 2021·Chemistry and Physics of Lipids·Carmelo TempraFabio Lolicato
Mar 2, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kyung-Won ParkJoanna L Jankowsky
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Julia PostJanine Kutzsche
Jun 18, 2021·ACS Chemical Neuroscience·Karoline SanturDieter Willbold
Jul 3, 2021·International Journal of Molecular Sciences·Luana Cristina CamargoAntje Willuweit
Jul 3, 2021·International Journal of Molecular Sciences·Julia PostAntje Willuweit

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Methods Mentioned

BETA
phage display
transgenic
ELISA
chip
Fluorescence
Assay
density gradient centrifugation

Software Mentioned

Ethovision
InVivoStat
sFIDAta
ImageJ
SigmaPlot
GraphPad Prism
LAS

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