JNK and ERK1/2 pathways have a dual opposite effect on the expression of BACE1

Abstract 

The activity of β-secretase (BACE1), the endo-protease essential for the production of amyloid β (Aβ) peptides, is increased in brain of late-onset sporadic Alzheimer's disease (AD), and oxidative stress is the potential cause of this event. Oxidative stress up-regulates the expression and the activity of BACE1 in cellular and animal models, through a mechanism that involves the increase of γ-secretase cleavage on APP and the activation of c-jun N-terminal kinase/activator protein 1 (JNK/AP1) pathway. We further characterized the cellular pathways that control BACE1 expression under oxidative stress. We investigated the involvement of extracellular signal regulated MAP kinase (ERK1/2) pathway in the regulation of BACE1 expression, since it has been recently shown that ERK1/2 is an endogenous regulator of the γ-secretase activity. We found that ERK1/2 pathway negatively modulates BACE1 expression and activity. Moreover, we observed that conditions that abrogate the γ-secretase activity favor the activation of signalling pathways that promote cell survival, such as ERK1/2 and the serine/threonine kinase Akt/protein kinase B (Akt). These data suggest that the positive or negative cellular responses to oxidative stress parallel the activities of the β- and the γ-secretase. ERK1/2 and JNK pathways are involved in this bipartite response, which can lead to neurodegeneration or neuroprotection depending on the cellular and environmental conditions or cooperation with other signalling pathways such as Akt cascade.

Abbreviations: BACE1, β-site APP cleaving enzyme, APP, amyloid precursor protein, Aβ, β amyloid, PS, presenilin, ERK1/2, extracellular signal regulated MAP kinase, Akt, serine/threonine kinase Akt/protein kinase B, SEK, stress-activated protein kinase-ERK kinase, PAK, p21-activated kinase, MKK, mitogen activated kinase kinase, MKKK, mitogen activated kinase kinase kinase, Ask1, apopstosis signal-regulating kinase, JNK, c-jun N-terminal kinase

Keywords: Alzheimer's disease, BACE1, γ-Secretase, Oxidative stress, ERK1/2, c-jun N-terminal kinase