Leptin inhibits amyloid ß-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 ß-protein (Aß) in the brain. The steady state level of Aß 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 Aß degradation. The major Aß-degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), which may promote Aß 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 Aß 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 Aß in primary cultured astrocytes. These results suggest that leptin suppresses Aß degradation by NEP through activation of ERK.