Impact of Cytokines and Chemokines on Alzheimer’s Disease Neuro-pathological Hallmarks
PURPOSE Interleukin-1beta (IL-1beta) and S100B calcium binding protein B (S100B) have been implicated in the pathogenesis of Alzheimer's disease. Both are present in and around senile plaques and have been shown to increase levels of amyloid precursor protein (APP) mRNA in vitro. However, it is not known how either of these substances affects APP in vivo. METHODS We have studied the effects of IL-1beta and S100B on the expression and processing of APP using a retinal-vitreal model. We have also investigated the effect of amyloid beta peptide (Abeta) on APP in the same system and the regulation of S100B production by Abeta and IL-1beta from retinal glial cells. RESULTS Retinal ganglion cells constitutively express APP. However, after intravitreal injection of IL-1beta or Abeta there was a marked reduction in APP levels as detected by Western blotting and IL-1beta produced a decrease in APP immunoreactivity (IR). Nissl staining showed that the integrity of the injected retinas was unchanged after injection. Two days after S100B injection, there was a small reduction in APP-IR but this was accompanied by the appearance of some intensely stained large ganglion cells and there was some up-regulation in APP holoprotein levels on Western blot. Seven days post-S100B injection, these large, highly stained cells had increased in number throughout the retina. Injection of Abeta and IL-1beta also caused an increase in S100B production within the retinal Müller glial cells. CONCLUSION These results support the hypothesis that S100B (a glial-derived neurotrophic factor) and IL-1beta (a pro-inflammatory cytokine) can modulate the expression and processing of APP in vivo and so may contribute to the progression of Alzheimer's disease.