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The Journal of Neuroscience, May 16, 2007, 27(20):5394-5404; doi:10.1523/JNEUROSCI.5047-06.2007

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Neurobiology of Disease
Connecting TNF- Signaling Pathways to iNOS Expression in a Mouse Model of Alzheimer's Disease: Relevance for the Behavioral and Synaptic Deficits Induced by Amyloid ß Protein

Rodrigo Medeiros,^1 * Rui D. S. Prediger,^1 * Giselle F. Passos,¹ Pablo Pandolfo,¹ Filipe S. Duarte,¹ Jeferson L. Franco,² Alcir L. Dafre,² Gabriella Di Giunta,³ Cláudia P. Figueiredo,³ Reinaldo N. Takahashi,¹ Maria M. Campos,⁴ and João B. Calixto¹

Departamentos de ¹Farmacologia and ²Ciências Fisiológicas, Centro de Ciências Biológicas, and ³Departamento de Anatomia Patológica, Hospital Universitário–Universidade Federal de Santa Catarina, 88049-900, Florianópolis, Santa Catarina, Brazil, and ⁴Faculdade de Odontologia, Pontifícia Universidade Católica do Rio Grande do Sul 90619-900, Rio Grande do Sul, Brazil

Correspondence should be addressed to Dr. João B. Calixto, Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco D, Caixa Postal 476, 88049-900, Florianópolis, Santa Catarina, Brazil. Email: calixto{at}farmaco.ufsc.br or Email: calixto3{at}terra.com.br

Increased brain deposition of amyloid ß protein (Aß) 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- (TNF-)-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 Aß_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- or iNOS reduced the cognitive deficit evoked by Aß_1–40 in mice. Similar results were obtained in TNF- receptor 1 and iNOS knock-out mice. Aß_1–40 administration induced an increase in TNF- expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Aß_1–40 led to activation of both JNK (c-Jun-NH₂-terminal kinase)/c-Jun and nuclear factor-B, resulting in iNOS upregulation in both brain structures. The anti-TNF- antibody reduced all of the molecular and biochemical alterations promoted by Aß_1–40. These results provide new insights in mouse models of AD, revealing TNF- and iNOS as central mediators of Aß action. These pathways might be targeted for AD drug development.

Key words: Alzheimer's disease; amyloid ß; inflammation; TNF-; iNOS; cognitive deficits

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Received Nov. 21, 2006; revised April 14, 2007; accepted April 17, 2007.

Correspondence should be addressed to Dr. João B. Calixto, Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco D, Caixa Postal 476, 88049-900, Florianópolis, Santa Catarina, Brazil. Email: calixto{at}farmaco.ufsc.br or Email: calixto3{at}terra.com.br

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