Title 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.
Author(s) Medeiros R, Prediger RD, Passos GF, Pandolfo P, Duarte FS, Franco JL, Dafre AL, Di Giunta G, Figueiredo CP, Takahashi RN, Campos MM, Calixto JB
Institution Departamento de Farmacologia, Centro de Ciências Biológicas, Hospital Universitário-Universidade Federal de Santa Catarina, 88049-900, Florianópolis, Santa Catarina, Brazil.
Source J Neurosci 2007 May 16; 27(20) :5394-404.
Abstract 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.
Language eng
Pub Type(s) Journal Article
Research Support, Non-U.S. Gov't
PubMed ID 17507561
Copyright notice
- TNFMedicine.com © 2007 Edward Lewis Tobinick MD, A Medical Corporation. All Rights Reserved.
Disclaimer
- The views expressed in this blog are my personal thoughts and opinions. I maintain this blog for my own use, to categorize important medical information for myself as it develops. Posts are for informational and educational purposes only. This blog does not constitute medical advice, and none of its posts should be interpreted or relied on as such. This blog does not constitute a solicitation for business. No claims, promises, or guarantees about the accuracy of the information herein are made. Sending me an e-mail does not create a physician-patient relationship. Many of the posts herein contain abstracts and citations which are publically available at www.pubmed.gov, the online medical article database from the National Library of Medicine(which has no affiliation with this site). Many of the posts contain information regarding off-label uses of biologic TNF antagonists. This website should not be interpreted to imply or explicitly make or propose any treatment recommendations. The off-label uses discussed on this website are uses which are, by definition, not FDA-approved. Therefore the safety and efficacy of these uses have not yet been confirmed nor endorsed by the FDA, and no recommendation regarding the use of these reported methods is inferred or implied by their inclusion on this website. Biologic TNF-anatagonists, such as etanercept, infliximab, and adalimumab can have serious adverse effects, such as death, infection, cytopenias, and may be associated with an increased risk of lymphoma, demyelinating disease, eye inflammation, and congestive heart failure. Medical consultation prior to their use is mandatory.
Patent Notice
- The following U.S. patents have been issued to Edward Tobinick MD concerning selected uses of certain biologic TNF antagonists and other cytokine antagonists for selected neurological and related indications in humans: 6,015,557; 6,177,077; 6,379,666; 6,419,934; 6,419,944; 6,423,321; 6,471,961; 6,428,787; 6,537,549; 6,982,089. Also Australian patent 758,523. Additional U.S. and foreign patents are pending.
« Role of tumour necrosis factor alpha, but not of cyclo-oxygenase-2-derived eicosanoids, on functional and morphological indices of dystrophic progression in mdx mice: a pharmacological approach. | Main | Inflammatory markers(TNF-alpha and IL-1) and the risk of Alzheimer disease: the Framingham Study. »
May 23, 2007
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