BACE1 Suppression by RNA Interference in Primary Cortical Neurons

Abstract

Extracellular deposition of amyloid-β (Aβ) aggregates in the brain represents one of the histopathological hallmarks of Alzheimer's disease (AD). Aβ peptides are generated from proteolysis of the amyloid precursor proteins (APPs) by β- and γ-secretases. β-Secretase (BACE1) is a type I integral membrane glycoprotein that can cleave APP first to generate C-terminal 99- or 89-amino acid membrane-bound fragments containing the N terminus of Aβ peptides (βCTF). As BACE1 cleavage is an essential step for Aβ generation, it is proposed as a key therapeutic target for treating AD. In this study, we show that small interfering RNA (siRNA) specifically targeted to BACE1 can suppress BACE1 (but not BACE2) protein expression in different cell systems. Furthermore, BACE1 siRNA reduced APP βCTF and Aβ production in primary cortical neurons derived from both wild-type and transgenic mice harboring the Swedish APP mutant. The subcellular distribution of APP and presenilin-1 did not appear to differ in BACE1 suppressed cells. Importantly, pretreating neurons with BACE1 siRNA reduced the neurotoxicity induced by H2O2 oxidative stress. Our results indicate that BACE1 siRNA specifically impacts on β-cleavage of APP and may be a potential therapeutic approach for treating AD.