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<p>Abstract</p> <p>Background</p> <p>Microglial function is modulated by several factors reflecting the numerous receptors expressed on the cell surface, however endogenous factors which contribute to the age-related increase in microglial activation remain largely unknown. One possible factor which may contribute is interferon-γ (IFNγ). IFNγ has been shown to increase in the aged brain and potently activates microglia, although its endogenous cell source in the brain remains unidentified.</p> <p>Methods</p> <p>Male Wistar rats were used to assess the effect of age and amyloid-β (Aβ) on NK cell infiltration into the brain. The effect of the anti-inflammatory compound, atorvastatin was also assessed under these conditions. We measured cytokine and chemokine (IFNγ, IL-2, monocyte chemoattractant protein-1 (MCP-1) and IFNγ-induced protein 10 kDa (IP-10)), expression in the brain by appropriate methods. We also looked at NK cell markers, CD161, NKp30 and NKp46 using flow cytometry and western blot.</p> <p>Results</p> <p>Natural killer (NK) cells are a major source of IFNγ in the periphery and here we report the presence of CD161⁺NKp30⁺cells and expression of CD161 and NKp46 in the brain of aged and Aβ-treated rats. Furthermore, we demonstrate that isolated CD161⁺cells respond to interleukin-2 (IL-2) by releasing IFNγ. Atorvastatin, the HMG-CoA reductase inhibitor, attenuates the increase in CD161 and NKp46 observed in hippocampus of aged and Aβ-treated rats. This was paralleled by a decrease in IFNγ, markers of microglial activation and the chemokines, MCP-1 and IP-10 which are chemotactic for NK cells.</p> <p>Conclusions</p> <p>We propose that NK cells contribute to the age-related and Aβ-induced neuroinflammatory changes and demonstrate that these changes can be modulated by atorvastatin treatment.</p>