Abstract
BackgroundAlzheimer's disease (AD) pathology shows characteristic 'plaques' rich in amyloid beta (Aβ) peptide deposits. Inflammatory process-related proteins such as pro-inflammatory cytokines have been detected in AD brain suggesting that an inflammatory immune reaction also plays a role in the pathogenesis of AD. Glial cells in culture respond to LPS and Aβ stimuli by upregulating the expression of cytokines TNF-α, IL-1β, and IL-6, and also the expression of proinflammatory genes iNOS and COX-2. We have earlier reported that LPS/Aβ stimulation-induced ceramide and ROS generation leads to iNOS expression and nitric oxide production in glial cells. The present study was undertaken to investigate the neuroprotective function of AICAR (a potent activator of AMP-activated protein kinase) in blocking the pro-oxidant/proinflammatory responses induced in primary glial cultures treated with LPS and Aβ peptide.MethodsTo test the anti-inflammatory/anti-oxidant functions of AICAR, we tested its inhibitory potential in blocking the expression of pro-inflammatory cytokines and iNOS, expression of COX-2, generation of ROS, and associated signaling following treatment of glial cells with LPS and Aβ peptide. We also investigated the neuroprotective effects of AICAR against the effects of cytokines and inflammatory mediators (released by the glia), in blocking neurite outgrowth inhibition, and in nerve growth factor-(NGF) induced neurite extension by PC-12 cells.ResultsAICAR blocked LPS/Aβ-induced inflammatory processes by blocking the expression of proinflammatory cytokine, iNOS, COX-2 and MnSOD genes, and by inhibition of ROS generation and depletion of glutathione in astroglial cells. AICAR also inhibited down-stream signaling leading to the regulation of transcriptional factors such as NFκB and C/EBP which are critical for the expression of iNOS, COX-2, MnSOD and cytokines (TNF-α/IL-1β and IL-6). AICAR promoted NGF-induced neurite growth and reduced neurite outgrowth inhibition in PC-12 cells treated with astroglial conditioned medium.ConclusionThe observed anti-inflammatory/anti-oxidant and neuroprotective functions of AICAR suggest it as a viable candidate for use in treatment of Alzheimer's disease.
Highlights
Alzheimer's disease (AD) pathology shows characteristic 'plaques' rich in amyloid beta (Aβ) peptide deposits
AICAR attenuates LPS- and Aβ peptide-induced expression of cytokines and iNOS, and nitric oxide (NO) production in glial cells It has been suggested that, in the CNS, activated microglia and astrocytes are linked to neurodegeneration as a result of expression of inflammatory mediators by these glial cells [6,28,29]
As evident from (Fig. 1a,c,e and 1g) and 2, Aβ significantly upregulated the LPS-induced production of cytokines TNF-α, IL-1β, IL-6 and nitric oxide (NO) in glial cells, http://www.jneuroinflammation.com/content/2/1/21
Summary
Alzheimer's disease (AD) pathology shows characteristic 'plaques' rich in amyloid beta (Aβ) peptide deposits. All major pro-inflammatory cytokines with the exception of IFN-γ (TNF-α, IL-1 and IL-6) have been detected in AD brain suggesting that an inflammatory immune reaction plays a role in the pathogenesis of AD [3,4]. In vitro treatment of glial cells with LPS/Aβ peptides induces cytokines (TNF-α, IL-1β), and leads to the release of NO by induction of iNOS, as a function of innate immune response (for a detailed review see [6,11]). The expression of iNOS leading to production of nitric oxide and, as a result, generation of peroxynitrite (a reaction product of the superoxide anion and nitric oxide) under oxidative stress conditions has been implicated in the extensive neuronal damage of several neurological disorders including AD [12,13]. The mechanisms of pro-inflammatory cytokinemediated oxidative stress (or vice versa) may be the potential target(s) for AD therapeutics
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