Leptin inhibits amyloid β-protein degradation through decrease of neprilysin expression in primary cultured astrocytes

Pathogenesis of Alzheimer's disease (AD) is characterized by accumulation of extracellular deposits of amyloid beta-protein (A beta) in the brain. The steady state level of A beta in the brain is determined by the balance between its production and removal; the latter occurring through egress across blood and CSF barriers as well as A beta degradation. The major A beta-degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), which may promote A beta deposition in patients with sporadic late-onset AD. Epidemiological studies have suggested an inverse relationship between the adipocytokine leptin levels and the onset of AD. However, the mechanisms underlying the relationship remain uncertain. We investigated whether leptin is associated with A beta degradation by inducing NEP and IDE expression within primary cultured astrocytes. Leptin significantly decreased the expression of NEP but not IDE in a concentration- and time-dependent manner through the activation of extracellular signal-regulated kinase (ERK) in cultured rat astrocytes. Furthermore, leptin inhibited the degradation of exogenous A beta in primary cultured astrocytes. These results suggest that leptin suppresses A beta degradation by NEP through activation of ERK. (C) 2014 Elsevier Inc. All rights reserved.