title: The multi-target effects of CNI-1493: convergence of anti-amylodogenic and anti-inflammatory properties in animal models of Alzheimer's disease.
abstract: After several decades of Alzheimer's disease (AD) research and failed clinical trials, one can speculate that targeting a single pathway is not sufficient. However, a cocktail of novel therapeutics will constitute a challenging clinical trial. A more plausible approach will capitalize on a drug that has relevant and synergistic multiple-target effects in AD. We have previously demonstrated the efficacy of CNI-1493 in the CRND8 transgenic AD mouse model. Similar to many anti-inflammatory drugs that were tested in preclinical model of AD, it was speculated that the significant effect of CNI-1493 is due to its established anti-inflammatory properties in rodents and humans. In the present study, we set out to elucidate the protective mechanism of CNI-1493 as a drug simultaneously targeting several aspects of AD pathology. Using C1213, a highly similar analogue of CNI-1493 that lacks anti-inflammatory properties, we show that both compounds directly interact with soluble and insoluble Amyloid β (Aβ) aggregates and attenuate Aβ cytotoxicity in vitro. Additionally, CNI-1493 and C1213 ameliorated Aβ-induced behavioral deficits in nematodes. Finally, C1213 reduced Aβ plaque burden and cognitive deficits in transgenic CRND8 mice to a similar extent as previously shown with CNI-1493. Taken together, our findings suggest anti-amyloidogenic activity as a relevant component for the in-vivo efficacy of CNI-1493 and its analogue C1213. Thus, CNI-1493, a drug with proven safety in humans, is a viable candidate for novel multi-target therapeutic approaches to AD.
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, 350 Community drive, Manhasset, NY 11030 USA.|Elmezzi Graduate School of Molecular Medicine, The Feinstein Institute for Medical Research, 350 Community drive, Manhasset, NY, 11030, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Sankowski
authors.affiliation: Institute of Neuropathology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Herring
authors.affiliation: Institute of Neuropathology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Keyvani
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacherstraße 64, D-79106 Freiburg Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Frenzel
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, 350 Community drive, Manhasset, NY 11030 USA.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Medical Sociology and Social Medicine, Philipps-University of Marburg, Karl-von-Frisch-Str. 8, 35043 Marburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Röskam
authors.affiliation: Department of Neurology, Faculty of Medicine, Philipps-University, Baldingerstraße, 35043 Marburg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Noelker
authors.affiliation: Institute of Immunology, Philipps-University Marburg, Hans-Meerwein-Str., 35043 Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bacher
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, 350 Community drive, Manhasset, NY 11030 USA.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
keywords: Amyloid beta; Caenorhabditis elegans; Cognition; Memory; Neuroinflammation; Semapimod; Transgenic Mouse