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

Abstract
Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid beta protein (Abeta) 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 Abeta assembly and protects neuronal cells from the toxic effect of soluble Abeta oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Abeta 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 Abeta accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.
AuthorsMichael Bacher, Richard Dodel, Bayan Aljabari, Kathy Keyvani, Philippe Marambaud, Rakez Kayed, Charles Glabe, Nicole Goertz, Anne Hoppmann, Norbert Sachser, Jens Klotsche, Susanne Schnell, Lars Lewejohann, Yousef Al-Abed
JournalThe Journal of experimental medicine (J Exp Med) Vol. 205 Issue 7 Pg. 1593-9 (Jul 07 2008) ISSN: 1540-9538 [Electronic] United States
PMID18573905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amyloid beta-Protein Precursor
  • Anti-Inflammatory Agents, Non-Steroidal
  • Hydrazones
  • semapimod
Topics
  • Alzheimer Disease (drug therapy, genetics, metabolism, pathology, physiopathology)
  • Amyloid beta-Protein Precursor (biosynthesis, genetics)
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
  • Dose-Response Relationship, Drug
  • Hippocampus (metabolism, pathology, physiopathology)
  • Humans
  • Hydrazones (pharmacology)
  • Mice
  • Mice, Transgenic
  • Microglia (metabolism, pathology)
  • Time Factors

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