Amyloid-beta peptides induce several chemokine mRNA expressions in the primary microglia and Ra2 cell line via the PI3K/Akt and/or ERK pathway.
ABSTRACT Alzheimer's disease (AD) is characterized by the presence of senile plaques composed primarily of amyloid-beta peptide (Abeta) in the brain. Microglia have been reported to surround these Abeta plaques, which have opposite roles, provoking a microglia-mediated inflammatory response that contributes to neuronal cell loss or the removal of Abeta and damaged neurons. To perform these tasks microglia migrate to the sites of Abeta secretion. We herein analyzed the process of chemokine expression induced by Abeta stimulation in primary murine microglia and Ra2 microglial cell line. We found that Abeta1-42 induced the expressions of CCL7, CCL2, CCL3, CCL4 and CXCL2 in the microglia. The signal transduction pathway for the expression of CCL2 and CCL7 mRNA induced by Abeta1-42 was found to depend on phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK), whereas the pathway for CCL4 depended only on PI3K/Akt. These inflammatory chemokine expressions by Abeta stimulation emphasize the contribution of neuroinflammatory mechanisms to the pathogenesis of AD.
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ABSTRACT: The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that can sense environmental stimuli such as growth factors, energy state, and nutrients. It is essential for cell growth, proliferation, and metabolism, but dysregulation of mTOR signaling pathway is also associated with a number of human diseases. Encouraging data from experiments have provided sufficient evidence for the relationship between the mTOR signaling pathway and Alzheimer's disease (AD). Upregulation of mTOR signaling pathway is thought to play an important role in major pathological processes of AD. The mTOR inhibitors such as rapamycin have been proven to ameliorate the AD-like pathology and cognitive deficits effectively in a broad range of animal models. Application of mTOR inhibitors indicates the potential value of reducing mTOR activity as an innovative therapeutic strategy for AD. In this review, we will focus on the recent process in understanding mTOR signaling pathway and the vital involvement of this signaling pathway in the pathology of AD, and discuss the application of mTOR inhibitors as potential therapeutic agents for the treatment of AD.Molecular Neurobiology 07/2013; · 5.47 Impact Factor
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ABSTRACT: The neuroinflammation induced by amyloid-beta peptide (Aβ) is one of the key events in Alzheimer's disease (AD) progress in which microglia are the main cells involved. Berberine, one of the major constituents of Chinese herb Rhizoma coptidis, is known for its anti-inflammatory, anti-oxidative and anti-microbial activity. In this study, we examined the effects and possible underlying mechanisms of berberine in Aβ-induced neuroinflammation using murine primary microglia cells and cultured BV2 microglia cells. The effects of berberine on Aβ-stimulated inflammatory factor expression and secretion were examined using RT-PCR and ELISA analysis. The signal pathways involved in berberine's effects were also investigated using Western blot and immunofluorescence analysis. In primary microglial and BV2 cells, berberine treatment significantly inhibited Aβ-stimulated production of interleukin-6 and monocyte chemotactic protein-1. Berberine treatment down-regulated the expression of cyclo-oxygenase-2 and induced nitric oxide synthase in these cells. Moreover, berberine strongly inhibited the nuclear factor-kappaB (NF-κB) activation, presumably through blocking the phosphoinositide 3-kinase/protein kinase B and mitogen-activated protein kinase signalling pathways. Our data indicated berberine is a potent suppressor of neuroflammation, presumably through inhibition of NF-κB activation, and suggested berberine has therapeutic potential for the treatment of neuroinflammation that is involved in neurological diseases such as AD.The Journal of pharmacy and pharmacology. 10/2012; 64(10):1510-21.
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ABSTRACT: The detrimental effect of activation of the chemokine CCL4/MIP-1β on neuronal integrity in patients with HIV-associated dementia has directed attention to the potential role of CCL4 expression and regulation in Alzheimer disease. Here, we show that CCL4 mRNA and protein are overexpressed in the brains of APPswe/PS1ΔE9 (APP/PS1) double-transgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from nontransgenic littermates or single-mutant controls. Increased levels of CCL4 mRNA and protein directly correlated with the age-related progression of cerebral amyloid-β (Aβ) levels in APP/PS1 mice. We also found significantly increased expression of activating transcription factor 3 (ATF3), which was positively correlated with age-related Aβ deposition and CCL4 in the brains of APP/PS1 mice. Results from chromatin immunoprecipitation-quantitative polymerase chain reaction confirmed that ATF3 binds to the promoter region of the CCL4 gene, consistent with a potential role in regulating CCL4 transcription. Finally, elevated ATF3 mRNA expression in APP/PS1 brains was associated with hypomethylation of the ATF3 gene promoter region. These observations prompt the testable hypothesis for future study that CCL4 overexpression, regulated in part by hypomethylation of the ATF3 gene, may contribute to neuropathologic progression associated with amyloid deposition in Alzheimer disease.Journal of neuropathology and experimental neurology. 03/2014;