Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-β onto the hippocampus in vivo

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Abstract

The purpose of this study was to describe—following the injection of a single intracerebral dose of fibrillar amyloid-β1–40 in vivo—some correlations between proinflammatory cytokines and oxidative stress indicators in function of time, as well as how these variables fit in a regression model. We found a positive, significant correlation between interleukin (IL)-1β or IL-6 and the activity of the glutathione peroxidase enzyme (GSH-Px), but IL-1β or IL-6 maintained a strong, negative correlation with the lipid peroxidation (LPO). The first 12 h marked a positive correlation between IL-6 and tumor necrosis factor-alpha (TNF-α), but starting from the 36 h, this relationship became negative. We found also particular patterns of behavior through the time for IL-1β, nitrites and IL-6, with parallel or sequential interrelationships. Results shows clearly that, in vivo, the fibrillar amyloid-β (Aβ) disrupts the oxidative balance and initiate a proinflammatory response, which in turn feeds the oxidative imbalance in a coordinated, sequential way. This work contributes to our understanding of the positive feedbacks, focusing the “cytokine cycle” along with the oxidative stress mediators in a complex, multicellular, and interactive environment.

Introduction

Depending on the experimental paradigm, there seems to be significant variability in terms of oxidative stress and neuroinflammatory responses to amyloid-β peptide (Aβ), a relevant factor in the pathogenesis of Alzheimer's disease (AD) Yan et al., 1999, Akiyama et al., 2000, Atwood et al., 2003. Variations in reports obey several conditions as the size of the amyloid fragment, type of model (in vitro, in vivo, transgenics), as well as the time of experimentation (Atwood et al., 2003). For example, Aβ25–35 (truncated form of amyloid-β spanning residues 25–35) plus interferon-gamma (IFN-γ) activate microglia in vitro to produce reactive nitrogen intermediates and high concentrations of tumor necrosis factor-alpha (TNF-α) Meda et al., 1995, Goodwin et al., 1995, Meda et al., 1999, Rogers et al., 2002. However, Aβ25–35 is not found in vivo (Seubert et al., 1992). It is noticeable that cellular responses to Aβ25–35, compared with the complete Aβ fragment (Aβ1–40 or Aβ1–42) or some other different Aβ fragments, often differ Shin et al., 1997, Yan et al., 1999, Szczepanik et al., 2001, Lue et al., 2001. Moreover, IFN-γ, which is a prerequisite for Aβ-induced nitric oxide (NO) generation in vitro, is not required in vivo Szczepanik et al., 2001, Ishii et al., 2000. Aβ25–35 fragment lacks the aminoterminus, which is critical for the cellular binding and consequent respiratory burst activation of human macrophages (Van Muiswinkel et al., 1999).

Depending on the experimental paradigm, there are also differences with regard to interleukins. For example, significant dose-dependent increases in the production of pro-interleukin-1β (pro-IL-1β), interleukin-6 (IL-6), TNF-α, among others, were observed after exposure just to pre-aggregated Aβ1–42 in isolated microglia from brains of patients with AD (Lue et al., 2001). However, in monotypic microglial cultures a strong proinflammatory response requires the presence of augmenting factors (e.g. IFN-γ or LPS) plus Aβ Rogers et al., 2002, Goodwin et al., 1995, Meda et al., 1995, Nakamura et al., 1999, Gasic-Milenkovic et al., 2003.

We tried to reproduce the oxidative-neuroinflammatory phenomena in response to the fibrillar Aβ1–40 deposition acting at an early step in the cascade of events in Aβ-associated cellular dysfunction, assuming that oxidative stress and the neuroinflammatory response are bidirectional events. Immune activation and inflammatory cascades have been linked to the pathogenic mechanisms in AD McGeer and McGeer, 2001, Akiyama et al., 2000. The upregulation of IL-1, IL-6 and TNF-α expression has been repeatedly observed in brains from individuals with AD Griffin et al., 1995, Patterson, 1995, Akiyama et al., 2000, and anti-inflammatory agents have been shown to slow the progression of AD (Scarpini et al., 2003). This inflammatory potential in the brain, even just by aging (Terao et al., 2002), contribute to neurodegenerative diseases. Physiologically, the cellular expression of cytokines in the CNS is strictly controlled; however, under certain pathological conditions such as oxidative stress, the expression of various cytokine genes may become spatially and temporally modified (Szelenyi, 2001). We performed a time-dependent correlation, along 84 h, between oxidative stress indicators such as nitrites, lipid peroxidation (LPO), as well as the activity of the glutathione peroxidase enzyme (GSH-Px) against levels of IL-1β, IL-6, and TNF-α.

Section snippets

Animals

Male Wistar rats (280; 3-month-old) were housed in pairs in a colony room on a 12:12 dark/light cycle with lights off at 20:00 h; food and water were provided ad libitum. The rats were divided into five groups, with four controls: (1) intact rats, (2) only surgically manipulated, (3) PBS-injected (PBS), (4) scrambled-Aβ40–1 (sAβ) injected rats, and (5) the experimental group of fibrillar neurotoxic-Aβ1–40-injected rats (fAβ). Surgical and animal care procedures were performed with strict

Nitrites and LPO products following fAβ-injection

Nitrites and LPO levels were significantly increased in brains of fAβ-injected rats compared against the control groups. fAβ-injected rats had nitrite levels higher than any other group (Fig. 1). Differences were significant (p<0.0001), particularly during the intervals of 12 and 60 h, when fAβ-induced nitrites rose 300% above the levels observed in the sAβ-injected rats, and 450% above nitrite levels in brains of intact rats. It was noticeable that there were two peaks of activity, first

Discussion

In vivo and in situ experimental conditions provide a complex, multicellular, and interactive environment Szczepanik et al., 2001, Ishii et al., 2000, Hartley et al., 1999, Weldon et al., 1998, which it can make available new insights, possibly along the lines suggested by in vitro results Rogers et al., 2002, Yan et al., 1999. In order to reproduce oxidative and proinflammatory effects, we used Aβ1–40 because it is the predominant product of the amyloid-β precursor protein (βAPP) processing

Acknowledgments

This work was supported by the Consejo Nacional de Ciencia y Tecnologı&#x0301;a [CONACYT], México, and the Instituto Mexicano del Seguro Social [IMSS].

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