The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer's disease

Background: Alzheimer's disease (AD) is characterized by senile plaques, extracellular deposits composed primarily of amyloid-beta (A beta), and neurofibrillary tangles, which are abnormal intracellular inclusions containing hyperphosphorylated tau. The amyloid cascade hypothesis posits that the deposition of A beta in the brain parenchyma initiates a sequence of events that leads to dementia. However, the molecular process by which the extracellular accumulation of A beta peptides promotes intracellular pathologic changes in tau filaments remains unclear. To elucidate this process, we presumed that astrocytes might trigger neuronal reactions, leading to tau phosphorylation. In this study, we examined AD pathology from the perspective of the astrocyte-neuron interaction. Results: A cytokine-array analysis revealed that A beta stimulates astrocytes to release several chemical mediators that are primarily related to inflammation and cell adhesion. Among those mediators, insulin-like growth factor (IGF)-binding protein 3 (IGFBP-3) was highly upregulated. In AD brains, the expression of IGFBP-3 was found to be increased by western blot analysis, and increased expression of IGFBP-3 was observed in astrocytes via fluorescence microscopy. In addition, we reproduced the increase in IGFBP-3 after treatment with A beta using human astrocytoma cell lines and found that IGFBP-3 was expressed via calcineurin. In AD brains, the activated forms of calcineurin were found to be increased by western blot analysis, and increased expression of calcineurin was observed in astrocytes via fluorescence microscopy. When Ser9 of glycogen synthase kinase-3 beta (GSK-3 beta) is phosphorylated, GSK-3 beta is controlled and tau phosphorylation is suppressed. A beta suppresses the phosphorylation of GSK-3 beta, leading to tau phosphorylation. In this study, we found that IGF-I suppressed tau phosphorylation induced by A beta, although IGFBP-3 inhibited this property of IGF-I. As a result, IGFBP-3 contributed to tau phosphorylation and cell death induced by A beta. Conclusions: Our study suggested that calcineurin in astrocytes was activated by A beta, leading to IGFBP-3 release. We further demonstrated that IGFBP-3 produced by astrocytes induced tau phosphorylation in neurons. Our study provides novel insights into the role of astrocytes in the induction of tau phosphorylation and suggests that IGFBP-3 could be an important link between A beta and tau pathology and an important therapeutic target.