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

Pontifícia Universidade Católica do Rio Grande do Sul, Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 06/2007; 27(20):5394-404. DOI: 10.1523/JNEUROSCI.5047-06.2007
Source: PubMed

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.

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    • "Similar to those observations, in the present study we observed that iNOS KO mice exhibited increased freezing behavior in the CFC and that the preferential nNOS inhibitor 7-NI attenuated this behavior . Although it is not possible to completely disregard the interference of learning deficits in our results, previous study failed to find deficits in iNOS KO mice tested in the Morris water maze paradigm (Medeiros et al., 2007). iNOS is not only expressed in the central nervous system during inflammatory conditions but is also present at basal levels in certain brain regions (Amitai, 2010) such as the HIP (Montezuma et al., 2011). "
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    • "This has lead to a move toward considering anti-TNFα as a therapy for Alzheimer's dementia (Cheng et al., 2014) Auanofin, a gold—containing medication and established treatment for RA, dampens inflammation through manipulation of the antiand pro-inflammatory interleukin balance. Interestingly a recent in vitro study has demonstrated a reduced production of cytotoxic mediators by microglia in response to gold therapy (Medeiros et al., 2007). Diamond and Tracey recently proposed the concept of the immunological homunculus of the brain (Diamond and Tracey, 2011) where the brain acts as a sensory organ, allowing real-time transmission of information such as infections, tissue damage and inflammation to the central nervous system. "
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    • "This contrasts previous reports where continuous peripheral TNF-a antagonism in RA patients improved cognition (Chen et al, 2010), suggesting that chronic rather than a single dose administration is needed to achieve such effects. However, it should be noted that Tobinick et al (2006) and Tobinick and Gross, (2008) observed a rapid improvement in cognition in a small cohort of patients with Alzheimer's disease (AD) following a single dose of peri-spinal etanercept and was supported by animal research on AD models where antagonism of TNF-a by ICV injection had immediate effects on cognition (Medeiros et al, 2007). Additionally, these findings suggest that centrally administered etanercept is more effective in attenuating cognitive impairment in CNS disease models such as AD, which are associated with more substantial cognitive deficits, than in our peripheral inflammatory model induced with a single dose Central etanercept effects on behavior and neuroinflammation ML Camara et al of LPS. "
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