The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online June 23, 2008
doi:10.1084/jem.20060467
The Journal of Experimental Medicine, Vol. 205, No. 7, 1593-1599
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Bacher et al.
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BRIEF DEFINITIVE REPORT

 CNI-1493 inhibits Aβ production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease

Michael Bacher1, Richard Dodel1, Bayan Aljabari2, Kathy Keyvani4, Philippe Marambaud3, Rakez Kayed5, Charles Glabe5, Nicole Goertz6, Anne Hoppmann6, Norbert Sachser6, Jens Klotsche7, Susanne Schnell8, Lars Lewejohann6, and Yousef Al-Abed2

1 Department of Neurology, Philipps-University Marburg, 35039 Marburg, Germany
2 Laboratory of Medicinal Chemistry, 3 Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, The Feinstein Institute for Medical Research, Manhasset, NY 11030
4 Institute of Neuropathology, University Hospital Muenster, 48149 Muenster, Germany
5 Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697
6 Department of Behavioural Biology, University of Muenster, 48149 Muenster, Germany
7 Institute of Clinical Psychology and Psychotherapy, Technical University Dresden, 01187 Dresden, Germany
8 Department of Neurology, University of Bonn, 53105 Bonn, Germany

CORRESPONDENCE Yousef Al-Abed:yalabed{at}nshs.edu

Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid β protein (Aβ) peptide "oligomers" and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Aβ assembly and protects neuronal cells from the toxic effect of soluble Aβ oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Aβ deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Aβ accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.

M. Bacher and R. Dodel contributed equally to this paper.


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