Mild Oxidative Stress Induces Redistribution of BACE1 in Non-Apoptotic Conditions and Promotes the Amyloidogenic Processing of Alzheimer’s Disease Amyloid Precursor Protein

• DOI: 10.1371/journal.pone.0061246
• Publication Date: 2013-04-17T20:49:51Z
• Authors: Jiang-Li Tan; Qiao-Xin Li; Giuseppe D. Cicco...; Peter John Crouch; Janetta Gladys Cu...; Anthony Robert White; Genevieve Evin
• Keywords: Amyloid; Science; Immunoblotting; 610; Fluorescent Antibody Technique; Apoptosis; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; Centrifugation, Density Gradient; Animals; Aspartic Acid Endopeptidases; Cells, Cultured; Cerebral Cortex; Caspase 3; Q; R; Hydrogen Peroxide; Enzyme Activation; Mice, Inbred C57BL; Adaptor Proteins, Vesicular Transport; Oxidative Stress; Medicine; Amyloid Precursor Protein Secretases; Protein Processing, Post-Translational; Research Article

BACE1 is responsible for β-secretase cleavage of the amyloid precursor protein (APP), which represents first step in production β (Aβ) peptides. Previous reports, by us and others, have indicated that levels activity are increased brain cortex patients with Alzheimer's disease (AD). The association between oxidative stress (OS) AD has prompted investigations support potentiation expression enzymatic OS. Here, we established conditions to analyse effects mild, non-lethal OS on primary neuronal cultures, independently from apoptotic mechanisms were shown impair turnover. Six-hour treatment mouse cortical cells 10-40 µM hydrogen peroxide did not significantly compromise cell viability but it produce mild (mOS), as reactive radical species activation p38 kinase. endogenous mRNA altered these conditions, whereas a toxic H2O2 concentration (100 µM) caused an increase levels. Notably, mOS resulted C-terminal product APP, β-CTF. Subcellular fractionation techniques showed major rearrangement localization light denser fractions, resulting distribution fractions containing APP markers trans-Golgi network early endosomes. Collectively, data demonstrate does modify alters subcellular compartmentalization favour amyloidogenic processing thus offer new insight molecular events pathogenesis.