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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    ABSTRACT: Background: Inducible (iNOS) or neuronal (nNOS) nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since NO and endocannabinoids (ECBs) interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain NOS activity and/or changes in the ECB system. Thus, we investigated the expression and extinction of contextual fear conditioning (CFC) of iNOS knockout (KO) mice and possible involvement of ECBs in these responses. Methods: We evaluated the effects of a preferential nNOS inhibitor, 7-nitroindazol (7-NI), NOS activity and mRNA changes of nitrergic and ECB systems components in the medial prefrontal cortex (MPFC) and hippocampus (HIP) of wild-type (WT) and KO mice. The effects of URB597, an inhibitor of the FAAH enzyme, which metabolize the ECB anandamide, WIN55,212-2, a non-selective cannabinoid agonist, and AM281, a selective CB1 antagonist, on CFC were also evaluated. Results: CFC expression was similar in WT and KO mice, but KO presented extinction deficits and increased basal NOS activity in the MPFC. 7-NI decreased fear expression and facilitated extinction in WT and KO mice. URB597 decreased fear expression in WT mice and facilitated extinction in KO mice whereas WIN and AM281 increased it in WT mice. Non-conditioned KO mice showed changes in the mRNA expression of nitrergic and ECB system components in the MPFC and HIP that were modified by fear conditioning. Conclusion: These data reinforce the involvement of the NO and ECBs (anandamide) in stress-related disorders and point out to a deregulation of the ECB system in situations where NO signaling is increased. nitric oxide7-nitroindazoleURB597WIN55212-2AM281anandamideCB1 receptorsfear conditioningextinction © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(8). DOI:10.1093/ijnp/pyv005 · 5.26 Impact Factor
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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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    Frontiers in Neuroscience 11/2014; 8(357):1-11. DOI:10.3389/fnins.2014.00357 · 3.70 Impact Factor
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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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    ABSTRACT: Peripheral cytokines affect central nervous system (CNS) function, manifesting in symptoms of anxiety and cognitive decline. Although the peripheral blockage of tumor necrosis factor (TNF-α) has been effective in alleviating depression and rheumatoid arthritis, it is yet unknown whether central blockade of TNF-α is beneficial for immune challenged CNS function. This study investigated effects of central etanercept administration following a peripheral immune challenge on anxiety-like and cognition-like behaviours and microglia and astrocyte numbers. 12 week old C57BL/6 mice (n=40) were treated with either LPS or saline administered peripherally 24 hr before being treated with either etanercept or artificial CSF (aCSF) by intracerebroventricular injection. Mice underwent behavioural analyses for locomotion, memory and anxiety-like behaviour 24 hr post etanercept/aCSF treatment and tissue was collected to estimate numbers of hippocampal microglia and astrocytes. Following peripheral immune challenge with LPS, mice showed increased anxiety-like behaviour, which was significantly improved following treatment with etanercept (2-way ANOVA: Interaction: F(1,30=0.60, P=0.44; Saline/LPS challenge: F(1,30)=23.92, P<0.0001, etanercept vs aCSF: F(1,30)=11.09, P=0.0023,). For cognition, a significant interaction effect found by 2-way ANOVA (Interaction: F(1,20)=4.96, P=0.037, Saline/LPS challenge: F(1,20)=4.966, P=0.31, aCSF/etanercept treatment: F(1,20)=0.06, P=0.80) and post-hoc analysis revealed a significant decrease in cognition in LPS-aCSF compared to Sal-aCSF mice (P=0.038), but no significant difference was noted between LPS-aCSF and LPS-Etan mice (P>0.9). A significant reduction in the number of microglia within the hippocampus of these mice was noted (2-way ANOVA: Interaction: F(1,15)=11.41, P= 0.0041; Saline/LPS challenge: F(1,15)=50.13, P<0.0001, etanercept vs aCSF: F(1,15)=3.36, P=0.08,). Centrally administered etanercept improved anxiety-like behaviour, but not spatial memory under a peripheral immune challenge and was associated with a decrease in hippocampal microglia numbers. This suggests that etanercept recovers anxiety-like behaviour possibly mediated by a reduction of TNF-α related central inflammation.Neuropsychopharmacology accepted article peview online, 8 August 2014. doi:10.1038/npp.2014.199.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2014; 40(2). DOI:10.1038/npp.2014.199 · 8.68 Impact Factor
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