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 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: 6.34). 06/2007; 27(20):5394-404. DOI: 10.1523/JNEUROSCI.5047-06.2007
Source: PubMed


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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Available from: Rui D Prediger, Oct 22, 2015
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    • "Research studies demonstrated that the Aβ (1-42) accumulation initiates a series of cellular cascades including glial cell (microglia and astrocytes) activation (Lenaz et al., 1998; Seabrook et al., 2006; Medeiros et al., 2007). The exact mechanism behind Aβ induced neuroinflammation hypothesis is still unknown (Seabrook et al., 2006). "
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    ABSTRACT: Rationale: Alzheimer’s disease (AD) is a debilitating disease with complex pathophysiology. Amyloid beta (Aβ) (1-42) is a reliable model of AD that recapitulates many aspects of human AD. Objective: The present study has been designed to investigate the neuroprotective potential of Coenzyme Q10 (CoQ10) and its modulation with minocycline (microglial inhibitor) against Aβ (1-42) induced cognitive dysfunction in rats. Method: Intrahippocampal (i.h.) Aβ (1-42) (1µg/µl; 4µl/site) were administered followed by drug treatment with galantamine (2 mg/kg), CoQ10 (20 and 40 mg/kg), minocycline (50 and 100 mg/kg) and their combinations for a period of 21 days. Various neurobehavioral parameters followed by biochemical, acetylcholinesterase (AChE) level, proinflammatory markers (TNF-α), mitochondrial respiratory enzyme complexes (I-IV) and histopathological examinations were assessed. Results: Aβ (1-42) administration significantly impaired cognitive performance in Morris water maze (MWM) performance test, causes oxidative stress, raised AChE level, caused neuroinflammation, mitochondrial dysfunction and histopathological alterations as compared to sham treatment. Treatment with CoQ10 (20 and 40 mg/kg) and minocycline (50 and 100 mg/kg) alone for 21days significantly improved cognitive performance as evidenced by reduced transfer latency and increased time spent in target quadrant (TSTQ), reduced AChE activity, oxidative damage (reduced LPO, nitrite level and restored SOD, catalase and GHS levels), TNF-α level, restored mitochondrial respiratory enzyme complex (I, II, III, IV) activities and histopathological alterations as compared to control (Aβ (1-42) treated animals) group. Further, combination of minocycline (50 and 100 mg/kg) with CoQ10 (20 and 40 mg/kg) significantly modulate the protective effect of CoQ10 as compared to their effect alone. Conclusion: The present study suggests that the neuroprotective effect of CoQ10 could be due to its microglia inhibitory mechanism along with its mitochondrial restoring and anti-oxidant properties.
    Full-text · Article · Oct 2015 · Frontiers in Pharmacology
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    • "Studies have described a type of neuroinflammation induced by a single intracerebroventricular (i.c.v.) infusion of Ab 1–40 that mimics early phases of AD. Even though this acute infusion of this peptide in the brain of rodents is unable to induce all the pathological features of AD, it has been used as an experimental model for studying Ab toxicity, which induces an inflammatory response associated with deficits in learning and memory (Medeiros et al. 2007; Prediger et al. 2007, 2008; Takeda et al. 2009; Piermartiri et al. 2010). Of particular importance, we have shown that administration of atorvastatin (10 mg/kg, p.o.) for seven consecutive days after i.c.v. "
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    ABSTRACT: Deposition of amyloid-β (Aβ) peptides into specific encephalic structures has been pointed as an important event related to Alzheimer's disease pathogenesis and associated with activation of glial cells, neuroinflammation, oxidative responses, and cognitive deficits. Aβ-induced pro-oxidative damage may regulate the activity of glutamate transporters, leading to reduced glutamate uptake and, as a consequence, excitotoxic events. Herein, we evaluated the effects of the pretreatment of atorvastatin, a HMG-CoA reductase inhibitor, on behavioral and biochemical alterations induced by a single intracerebroventricular (i.c.v.) injection of aggregated Aβ1-40 in mice. Atorvastatin (10 mg/kg/day, p.o.) was administered through seven consecutive days before Aβ1-40 administration. Aβ1-40 caused significant cognitive impairment in the object-place recognition task (2 weeks after the i.c.v. injection) and this phenomenon was abolished by atorvastatin pretreatment. Ex vivo evaluation of glutamate uptake into hippocampal and cerebral cortices slices showed atorvastatin, and Aβ1-40 decreased hippocampal and cortical Na(+)-dependent glutamate uptake. However, Aβ1-40 increased Na(+)-independent glutamate uptake and it was prevented by atorvastatin in prefrontal cortex slices. Moreover, Aβ1-40 treatment significantly increased the cerebrocortical activities of glutathione reductase and glutathione peroxidase and these events were blunted by atorvastatin pretreatment. Reduced or oxidized glutathione levels were not altered by Aβ1-40 and/or atorvastatin treatment. These results extend the notion of the protective action of atorvastatin against neuronal toxicity induced by Aβ1-40 demonstrating that a pretreatment with atorvastatin prevents the spatial learning and memory deficits induced by Aβ in rodents and promotes changes in glutamatergic and antioxidant systems mainly in prefrontal cortex.
    Full-text · Article · Apr 2015 · Neurotoxicity Research
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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.
    Full-text · Article · Jan 2015 · The International Journal of Neuropsychopharmacology
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