Elsevier

Neuroscience Letters

Volume 468, Issue 2, 4 January 2010, Pages 151-155
Neuroscience Letters

The amyloid-β25–35 injection into the CA1 region of the neonatal rat hippocampus impairs the long-term memory because of an increase of nitric oxide

https://doi.org/10.1016/j.neulet.2009.10.087Get rights and content

Abstract

Alzheimer's disease (AD) is characterized by the amyloid-beta (Aβ) aggregation but it is unclear when this process begins. Previously, we showed that amyloid-β25–35 (Aβ(25–35)) increases the nitric oxide (NO) pathways and causes neurodegenerative effects in rats. The excessive increase of NO during brain development can promote a persistent oxidative stress, but the role of the Aβ(25–35) in the neonatal age and its effects over the long term is unclear. Our aim was to evaluate if the Aβ(25–35) injection on postnatal day 7 causes loss in spatial memory by NO pathways in adult rats. Our results showed that neonatal-Aβ(25–35) injection into the hippocampus (Hp) causes significant impairments in the spatial memory after 90 days. The NO levels were found increased and argynophilic in the Hp. Other evidence of neuronal damage was an increase of the immunoreactivity for 3-nitrotyrosine (3-NT) and the glial-fibrilar acid protein (GFAP) in the Hp of the Aβ(25–35) group. In contrast, these effects were blocked by the administration of L-NAME (inhibitor of nitric oxide synthase) before the injection of Aβ(25–35). The L-NAME plus Aβ(25–35) group showed a better performance in the spatial memory compared to the Aβ(25–35) group. In addition in this group we found a decrease of NO, 3-NT and neurodegeneration in the Hp compared to the Aβ(25–35) group. This finding is a novel result about the role of Aβ(25–35) during the neonatal stage that enhances the NO production, which appears to impair the spatial memory in adult rats.

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Acknowledgments

This work was supported in part by CONACYT (61205), INNN (15/06), UNAM PAPIIT IN214609 and IN212108 given to J.G. and the Laboratory of Neuropharmacology-BUAP grant (LNAB1-08) given to D.L. Thanks to Dr. Ellis Glazier for editing this English-language text.

References (22)

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    Our research group has studied the cellular mechanisms by which the Aβ(25–35) peptide could promote deterioration in learning and memory. Among the different pro-inflammatory proteins produced in response to the oxidative stress induced by Aβ(25–35) are inducible nitric oxide synthase (iNOS) and its enzymatic product, nitric oxide (NO●) (Limón et al., 2009a; Díaz et al., 2010, 2011, 2012), markers which are considered the most important neurotoxic effectors in AD (Togo et al., 2011). The participation of NO● in the neurodegenerative process induced by Aβ(25–35) has been demonstrated by inhibiting NOS (iNOS and nNOS) activity, resulting in decreased nitrite (a stable metabolite of NO●) concentration and improving learning and spatial memory (Díaz et al., 2011, 2014).

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    Thus, aggregated Aβ42 correlates with caspase-8 mRNA levels in the temporal region of AD-affected brains (Matsui et al., 2006) and is increased in damaged neurons (Ohyagi et al., 2000). A derivative fragment of Aβ (Aβ25–35), that is not consistently detectable in AD-affected brains but can mimic some of Aβ-related phenotypes (Diaz et al., 2010; Meunier, Leni, & Maurice, 2006), indeed promotes apoptosis in lymphocytes (Velez-Pardo, Ospina, & Jimenez del Rio, 2002) and in PC12 cells (Martin et al., 2001). This Aβ-mediated enhanced neurodegeneration also occurs in vivo in a mouse model of Alzheimer's disease (transgenic mice harboring a presenilin 1 mutation) where Aβ accumulation triggers retinal degeneration (Ning, Cui, To, Ashe, & Matsubara, 2008).

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    The dysfunction in the NO metabolism and the events of toxicity that this molecule enhances has been linked to neurodegeneration (Giasson et al., 2000; Stack et al., 2008), as our results have shown. Several authors have studied the effects of NO in the memory process in models of neurodegeneration, but now it appears that high amounts of nitrites could be a source of damage that promotes the nitrosative stress that enhances protein nitration and neuronal damage to cause memory impairment (Limón et al., 2009a,b; Díaz et al., 2010). The nNOS and iNOS immunoreactivity have been found over the chronic course of β-amyloid toxicity in the cortex of patients with AD (Fernández-Vizarra et al., 2004; Malinski, 2007).

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