Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein

Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-alpha (TNF...

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Bibliographic Details
Published in:The Journal of neuroscience 2007-05, Vol.27 (20), p.5394-5404
Main Authors: Medeiros, Rodrigo, Prediger, Rui D S, Passos, Giselle F, Pandolfo, Pablo, Duarte, Filipe S, Franco, Jeferson L, Dafre, Alcir L, Di Giunta, Gabriella, Figueiredo, Cláudia P, Takahashi, Reinaldo N, Campos, Maria M, Calixto, João B
Format: Article
Language:English
Subjects:
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Amyloid beta-Peptides - administration & dosage
Amyloid beta-Peptides - physiology
Animals
Disease Models, Animal
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Enzymologic - physiology
Injections, Intraventricular
Male
Memory Disorders - chemically induced
Memory Disorders - enzymology
Mice
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide Synthase Type II - biosynthesis
Nitric Oxide Synthase Type II - genetics
Signal Transduction - drug effects
Signal Transduction - physiology
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - physiology
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Summary:Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-alpha (TNF-alpha)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of both in vivo and in vitro approaches. The intracerebroventricular injection of Abeta(1-40) in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-alpha or iNOS reduced the cognitive deficit evoked by Abeta(1-40) in mice. Similar results were obtained in TNF-alpha receptor 1 and iNOS knock-out mice. Abeta(1-40) administration induced an increase in TNF-alpha expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Abeta(1-40) led to activation of both JNK (c-Jun-NH2-terminal kinase)/c-Jun and nuclear factor-kappaB, resulting in iNOS upregulation in both brain structures. The anti-TNF-alpha antibody reduced all of the molecular and biochemical alterations promoted by Abeta(1-40). These results provide new insights in mouse models of AD, revealing TNF-alpha and iNOS as central mediators of Abeta action. These pathways might be targeted for AD drug development.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.5047-06.2007