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.
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Authors | Michael 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 |
Journal | The Journal of experimental medicine
(J Exp Med)
Vol. 205
Issue 7
Pg. 1593-9
(Jul 07 2008)
ISSN: 1540-9538 [Electronic] United States |
PMID | 18573905
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amyloid beta-Protein Precursor
- Anti-Inflammatory Agents, Non-Steroidal
- Hydrazones
- semapimod
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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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