Insulin-signaling Pathway Regulates the Degradation of Amyloid β-protein via Astrocytes

Alzheimer's disease (AD) has been considered as a metabolic dysfunction disease associated with impaired insulin signaling. Determining the mechanisms underlying insulin signaling dysfunction and resistance in AD will be important for its treatment. Impaired clearance of amyloid-β peptide (Aβ) significantly contributes to amyloid accumulation, which is typically observed in the brain of AD patients. Reduced expression of important Aβ-degrading enzymes in the brain, such as neprilysin (NEP) and insulin-degrading enzyme (IDE), can promote Aβ deposition in sporadic late-onset AD patients. Here, we investigated whether insulin regulates the degradation of Aβ by inducing expression of NEP and IDE in cultured astrocytes. Treatment of astrocytes with insulin significantly reduced cellular NEP levels, but increased IDE expression. The effects of insulin on the expression of NEP and IDE involved activation of an extracellular signal-regulated kinase (ERK)-mediated pathway. The reduction in cellular NEP levels was associated with NEP secretion into the culture medium, whereas IDE was increased in the cell membranes. Moreover, insulin-treated astrocytes significantly facilitated the degradation of exogenous Aβ within the culture medium. Interestingly, pretreatment of astrocytes with an ERK inhibitor prior to insulin exposure markedly inhibited insulin-induced degradation of Aβ. These results suggest that insulin exposure enhanced Aβ degradation via an increase in NEP secretion and IDE expression in astrocytes, via activation of the ERK-mediated pathway. The inhibition of insulin signaling pathways delayed Aβ degradation by attenuating alterations in NEP and IDE levels and competition with insulin and Aβ. Our results provide further insight into the pathological relevance of insulin resistance in AD development.