Understanding BACE1: essential protease for amyloid-β production in Alzheimer’s disease

Abstract

The identification of the aspartic protease BACE1 (beta-secretase) was a defining event in research aimed at understanding the molecular mechanisms that underlie Alzheimer's disease (AD) pathogenesis. This is because BACE1 catalyses the rate limiting step in the production of amyloid-beta (Abeta) the principal component of plaque pathology in AD, the excessive production of which is believed to be a primary cause of neurodegeneration, and cognitive dysfunction in AD. Subsequent discoveries showed that genetic deletion of BACE1 completely abolishes Abeta production and deposition in vivo, and that BACE1 activity is significantly increased in AD brain. In this review we present current knowledge on BACE1, discussing its structure, function and complex regulation with a view to understanding BACE1 function in the brain, and BACE1 as a target in blocking aberrant Abeta production in AD.

Nicotine Decreases Beta-Amyloid Through Regulating BACE1 Transcription in SH-EP1-α4β2 nAChR-APP695 Cells

“…Since NFjB, as a transcription factor, has been implicated in the induction of BACE1 expression [10], we hypothesized that NFjB may influence BACE1 promoter activity. To test this hypothesis, we assessed BACE1 promoter activity in SH-EP1-a4b2 nAChR-APP695 cells using dual luciferase reporter gene assay.…”

“…BACE1 and its activity are increased in the brains of sporadic and familial AD cases, and in various transgenic models of AD [7][8][9]. A more recent study has shown that BACE1 elevation occurred predominantly within neurons surrounding plaques in both AD and animal models of AD [10]. Presenilin proteins are the catalytic center of the c-secretase complex [2].…”

Molecular mechanisms of neuropathological changes in Alzheimer’s disease: a review

“…The human amyloid precursor protein (APP) was first identified in 1987 by several laboratories [20,64,57]. The APP gene was then mapped to chromosome 21 [58].…”

“…β-secretase 1 is a membrane-bound aspartyl protease with a characteristic type I transmembrane domain near C-terminus. The BACE gene is located on chromosome 11 and consists of nine exons coding for a protein of 501 amino acids [64]. β-secretase 1 pre-mRNA can undergo alternative splicing in exons 3 and 4, which results in the production of four alternative variants with 501, 476, 457, and 432 amino acids.…”

The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer’s Disease and Beyond

“…Hypoxic and oxidative cell stress, mediated by hypoxia-inducible factor 1α (HIF1α), the lipid peroxidation product hydroxy-non-enal (HNE), the c-JUN N-terminal kinase (JNK)/c-JUN pathway, and others, has been shown to increase BACE1 mRNA levels (Yasojima et al, 2001; Holsinger et al, 2002; Tamagno et al, 2005, 2008, 2009; Zhang et al, 2007). Not all previous work on the transcriptional and translational regulation of BACE1 can be cited at this point and we refer the reader to two excellent reviews for further information (Rossner et al, 2006; Stockley and O’Neill, 2008). However, most of these studies are based on in vitro observations.…”