Inflammatory response in the CNS: friend or foe?
Chronic inflammatory reactions are consistently present in neurodegeneration of Alzheimer’s type and are considered important factors that accelerate progression of the disease. Inflammatory reactions could be both beneficial and detrimental to the brain, depending on strengths of their activation in various stages of neurodegeneration. Mild activation of microglia and astrocytes usually reveals neuroprotective effects and ameliorates early symptoms of neurodegeneration; for instance, released cytokines help maintain synaptic plasticity and modulate neuronal excitability, and stimulated toll-like receptors(TLRs) promote neurogenesis and neurite outgrowth. However, strong activation of glial cells gives rise to cytokine overexpression/dysregulation, which accelerates neurodegeneration. TLRs and receptors for advanced glycation end product(RAGE), play a central role in perpetuation of inflammation. RAGE activation should be perceived as a primary mechanism which determines self-perpetuated chronic inflammation, and RAGE cooperation with TLRs amplifies inflammatory signaling. Altered mutual regulation of p53 protein, a major tumor suppressor, and NF-kB, the major regulation of inflammation, seems to be crucial for the shift from beneficial to detrimental effects of neuroinflammatory reactions in neurodegeneration. Therapeutic intervention in the p53-NF-kB axis and modulation of RAGE-TLR crosstalk activity are future challenges to cope with neurodegeneration.