Insulin-signaling Pathway Regulates the Degradation of Amyloid ß-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-ß peptide (Aß) significantly contributes to amyloid accumulation, which is typically observed in the brain of AD patients. Reduced expression of important Aß-degrading enzymes in the brain, such as neprilysin (NEP) and insulin-degrading enzyme (IDE), can promote Aß deposition in sporadic late-onset AD patients. Here, we investigated whether insulin regulates the degradation of Aß 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 Aß within the culture medium. Interestingly, pretreatment of astrocytes with an ERK inhibitor prior to insulin exposure markedly inhibited insulin-induced degradation of Aß. These results suggest that insulin exposure enhanced Aß 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 Aß degradation by attenuating alterations in NEP and IDE levels and competition with insulin and Aß. Our results provide further insight into the pathological relevance of insulin resistance in AD development.

Epigallocatechin gallate induces extracellular degradation of amyloid ß-protein by increasing neprilysin secretion from astrocytes through activation of ERK and PI3K pathways.

Amyloid-ß (Aß) production and clearance in the brain is a crucial focus of investigations into the pathogenesis of Alzheimer disease. Imbalance between production and clearance leads to accumulation of Aß. The important Aß-degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), and defective enzyme expression may facilitate Aß deposition in sporadic late-onset AD patients. It has been suggested that epigallocatechin gallate (EGCG), a member of the catechin family, might be an effective treatment for AD, because it has been shown to elevate NEP expression. Therefore, we examined whether catechins, which are functional components of common foods, could regulate the degradation of Aß by inducing NEP and IDE expression. We also investigated the role of catechins in activating intracellular signal transduction in astrocytes. Treatment of cultured rat astrocytes with EGCG significantly reduced the expression of NEP, but not IDE, in a concentration- and time-dependent manner. NEP expression in cultured astrocytes was suppressed by activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), and reduced NEP expression was accompanied by an increase of NEP release into the extracellular space (culture medium). Moreover, culture medium from EGCG-treated astrocytes facilitated the degradation of exogenous Aß. These results suggest that EGCG may have a beneficial effect on AD by activating ERK-and PI3K-mediated pathways in astrocytes, thus increasing astrocyte secretion of NEP and facilitating degradation of Aß.