Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-β onto the hippocampus in vivo
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 Tecnologı́a [CONACYT], México, and the Instituto Mexicano del Seguro Social [IMSS].
References (54)
- et al.
Inflammation and Alzheimer's disease
Neurobiol. Aging
(2000) - et al.
β-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology
Brain Res.
(2001) - et al.
Amyloid-β a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β
Brain Res. Rev.
(2003) - et al.
p38-dependent enhancement of cytokine-induced nitric-oxide synthase gene expression by heat shock protein 70
J. Biol. Chem.
(2000) - et al.
Differential regulation of astrocyte TNF-α expression by the cytokines TGF-β, IL-6 and IL-10
Int. J. Dev. Neurosci.
(1995) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding
Anal. Biochem.
(1976)The metallobiology of Alzheimer's disease
Trends Neurosci.
(2003)- et al.
Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients
Free Radic. Biol. Med.
(2002) - et al.
Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability
J. Biol. Chem.
(2002) - et al.
Reciprocal control of inflammatory cytokines, IL-1 and IL-6, and β-amyloid production in cultures
Neurosci. Lett.
(1995)
Unchanged levels of interleukins, neopterin, interferon-? and tumor necrosis factor-α in cerebrospinal fluid of patients with dementia of the Alzheimer type
Neurochem. Int.
Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal
Methods Enzymol.
Differential effects of amyloid peptides β1–40 and β25–35 injections into the rat nucleus basalis
Neuroscience
Long-term changes in the aggregation state and toxic effects of β-amyloid injected into the rat brain
Neuroscience
β-Amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway
Neurobiol. Dis.
Microglial release of nitric oxide by the synergistic action of β-amyloid and IFN-γ
Brain Res.
Mitochondrial function, GSH and iron in neurodegeneration and lewy body diseases
J. Neurol. Sci.
Inflammation, autotoxicity and Alzheimer's disease
Neurobiol. Aging
Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with β-amyloid25–35
J. Neuroimmunol.
Induction of cytokines in glial cells surrounding cortical β-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology
Int. J. Dev. Neurosci.
Generation and characterization of immortalized human microglial cell lines: expression of cytokines and chemokines
Neurobiol. Dis.
Lipopolysaccharide-induced microglial activation in culture: temporal profiles of morphological change and release of cytokines and nitric oxide
Neurosci. Res.
Cytokines in Alzheimer's disease and multiple sclerosis
Curr. Opin. Neurobiol.
Treatment of Alzheimer's disease: current status and new perspectives
Lancet Neurol.
Cytokines and the central nervous system
Brain Res. Bull.
Multiple signaling events in amyloid β-induced, oxidative stress-dependent neuronal apoptosis
Free Radic. Biol. Med.
Immune response gene expression increases in the aging murine hippocampus
J. Neuroimmunol.
Cited by (50)
Aβ dissociation by pectolinarin may counteract against Aβ-induced synaptic dysfunction and memory impairment
2023, Biochemical PharmacologyAntioxidant and antiinflammatory role of melatonin in Alzheimer's neurodegeneration
2020, Aging: Oxidative Stress and Dietary AntioxidantsNeurotheranostics as personalized medicines
2019, Advanced Drug Delivery ReviewsCitation Excerpt :All three lead to an overproduction Aβ42 which can undergo conformational changes that induce aggregation of soluble peptide fragments into large fibrils that become insoluble plaques [272](Fig. 3). Aβ plaque toxicity is mediated by multiple mechanisms that include, but are not limited to, oxidative stress, mitochondrial dysfunction, increased membrane permeability, microglial activation, synaptic dysfunction, and excitotoxicity [276-280]. The Aβ plaques first form in the basal cortex but spread gradually to most associative neocortical regions with the exception of the hippocampus [281].
Neuroinflammation induced by the peptide amyloid-β (25–35) increase the presence of galectin-3 in astrocytes and microglia and impairs spatial memory
2019, NeuropeptidesCitation Excerpt :This stablishes a relationship between hippocampal lesion via the Aβ25–35 peptide and spatial memory impairment recorded in the MWM task. The Aβ25–35 peptide causes cognitive deficit by facilitating several synaptic damage mechanisms (Lazcano et al., 2014; Ramírez et al., 2018), and inducing the activation of the nitric oxide (NO) pathway (Limón et al., 2009), oxidative stress (Butterfield et al., 2001), membrane lipid peroxidation (Butterfield et al., 2002; Gunn et al., 2016), mitochondrial dysfunction (Canevari et al., 1999), alterations in membrane permeability (Lin et al., 2001), excitotoxicity (Parameshwaran et al., 2008; Esposito et al., 2013), cholinotoxicity (Patricio-Martínez et al., 2016) and inflammation (Rosales-Corral et al., 2004; Diaz et al., 2012). These effects might thus contribute to dorsal hippocampus dysfunction and memory impairment.