Research articleEpigallocatechin-3-gallate prevents systemic inflammation-induced memory deficiency and amyloidogenesis via its anti-neuroinflammatory properties
Introduction
Alzheimer's disease (AD) is the most common cause of dementia, accounting for 50% to 75% of all cases [1], [2]. AD is pathologically characterized by senile plaques and neurofibrillary tangles in the brain. In particular, the senile plaques are extracellular aggregates of amyloid beta-peptide (Aβ) that are cleaved from the amyloid precursor protein (APP) [3]. Postmortem studies of AD brains also found a number of pathological abnormalities including a profound loss of synapses, microglial activation and inflammatory processes [4]. Previous studies with transgenic animals revealed that neuroinflammation also accelerates amyloidogenesis in the process of cerebral amyloid deposition [5], [6], [7], [8]. In the process of neuroinflammation, various cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, etc.], chemokines [monocyte chemotactic protein (MCP)-1, macrophage-derived inflammatory mediator (MIP)-α, etc.], oxygen free radicals and reactive nitrogen species [9], and eicosanoids such as leukotriene B4 and prostaglandins [10] are important signaling molecules of neuroinflammatory responses [11].
Intraperitoneal (ip) administration of lipopolysaccharide (LPS) can induce an immediate, strong and persistent up-regulation of proinflammatory cytokines IL-1β, IL-6 and TNF-α primarily from macrophages, and these proinflammatory cytokines exert neurobiological effects [12], suggesting that systemic inflammation can affect the neurobiological condition. Systemic administration of a single dose of LPS through ip injections induces neuroinflammation that persists for 10 months, which results in the progressive loss of dopaminergic neurons in the substantia nigra [13]. Mouton et al. [14] found that single ip injection of LPS induced elevation of several cytokines, such as IL-1β, IL-6 and TNF-α, in hippocampal tissue. Erickson and Banks [15] reported that single and three repeated ip injections of LPS increased release of neuroinflammatory-related cytokines and chemokines granulocyte colony-stimulating factor, IL-1α, IL-6, MCP-1, MIP-1α and TNF-α, in mouse brain. Those inflammatory components accelerate amyloidogenesis via up-regulation of the β-secretase level and activity [16], [17]. Recently, Jaeger et al. [18] reported that systemic injection of LPS increased brain influx of blood Aβ via alteration of low density lipoprotein receptor-related protein 1 (LRP-1) in mice brain. Our previous studies also showed that systemic administration of LPS could induce memory deficiency and Aβ accumulation through the elevation of β- and γ-secretase activities [19]. Moreover, administration of anti-inflammatory agents in AD patients could reduce amyloidogenesis, suggesting that neuroinflammation may cause the pathogenesis of AD via amyloidogenesis [20]. Thus, this animal model might be useful to study underlying mechanisms of neuroinflammation-associated development of AD.
Epigallocatechin-3-gallate (EGCG) is the most abundant biologically active compound in tea. Epidemiological studies have also suggested a positive relationship between consumption of EGCG and the prevention of AD [21]. Green tea extract or EGCG has been reported to attenuate Aβ-induced neurotoxicity in cultured human neuronal cell lines and to modulate both tau pathology and Aβ-mediated cognitive impairment in transgenic mice models of AD [22], [23], [24], [25], [26]. It was also reported that green tea has anti-β-secretase activity in vitro [27]. Moreover, Rezai-Zadeh et al. [22] reported that EGCG markedly elevated the α-secretase activity and promoted soluble APP-α production in the murine neuron-like cells transfected with the human Swedish mutant form of APP (SweAPP N2a cells), as well as in primary neurons derived from Swedish mutant APP-overexpressing mice (the Tg APPsw line 2576).
In our previous studies, we found that intracerebroventricular (icv) injection of LPS induced memory deficiency and Aβ accumulation through decreased α-secretase activity as well as elevation of the β- and γ-secretase activities, and these were all reduced by EGCG [28]. We previously also demonstrated that EGCG prevented amyloidogenesis via inhibition of β-secretase activity in Aβ-injected and presenilin2 mutant transgenic mice [28], [29]. Thus, we investigated preventive effect of EGCG on the systemic neuroinflammation model via ip injection of LPS, and we investigated the possible mechanisms of EGCG effects to improve the memory deficiency in systemic LPS-injected AD mice models.
Section snippets
EGCG
Green tea-derived flavonoid EGCG was purchased from Sigma-Aldrich (St. Louis, MO, USA). In our previous memory impairment animal model, 1.5 and 3 mg/kg EGCG treatment for 3 weeks showed a neuroprotective effect [28], [29]. Therefore, a similar dose of EGCG (1.5 and 3 mg/kg) was used in the present study, which is about 1.5 times more than the dose of human consumption. The daily human consumption of green tea is about 2 mg/kg (12 g×1% yield from green tea leaf/70 kg) [30]. The average water
Effect of EGCG on the LPS-induced memory impairment as determined by behavior tests
The memory-improving effect of EGCG was assessed in mice that were continuously administered with EGCG at a dose of 1.5 or 3 mg/kg/day daily for 3 weeks (from day 1 to day 28), and then they were ip injected with 250 μg/kg/day LPS for 1 weeks (from day 22 to day 28). The mice then performed the Morris water maze test after 15 training sessions (three times per day for 5 days) as shown in Fig. 1. Similar to previous findings [19], [28], the LPS injection retarded arriving at the location of the
Discussion
The most important finding in this study is that systemic administration of LPS caused memory impairment and that EGCG suppressed the amyloidogenesis through its anti-neuroinflammatory property via modulation of cytokine release in systemic LPS-induced in vivo and in vitro models, and resulted in ameliorated memory impairment.
Many epidemiological and experimental animal studies have suggested that neuroinflammation may contribute to the occurrence and progress of AD [37], [38], [39], [40].
Acknowledgments
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government [MEST] (MRC, 2010–0029480), by a grant (No. A101836) of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea and by a grant of the Korea Ministry of Education, Science and Technology (The Regional Core Research Program/Chungbuk BIT Research-Oriented University Consortium).
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