Regulation of β‐site APP‐cleaving enzyme 1 gene expression and its role in Alzheimer’s Disease

Abstract

J. Neurochem. (2012) 120 (Suppl. 1), 62–70. Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia. Neuritic plaques are the hallmark neuropathology in AD brains. Proteolytic processing of amyloid‐β precursor protein at the β site by beta‐site amyloid‐β precursor protein‐cleaving enzyme 1 (BACE1) is essential to generate Aβ, a central component of the neuritic plaques. BACE1 is increased in some sporadic AD brains, and dysregulation of BACE1 gene expression plays an important role in AD pathogenesis. This review will focus on the regulation of BACE1 gene expression at the transcriptional, post‐transcriptional, translation initiation, translational and post‐translational levels, and its role in AD pathogenesis. Further studies on BACE1 gene expression regulation will greatly contribute to our understanding of AD pathogenesis and reveal potential novel approaches for AD prevention and drug development.

Nuclear Factor-κB Regulates βAPP and β- and γ-Secretases Differently at Physiological and Supraphysiological Aβ Concentrations

“…* This work was supported by the Fondation pour la Recherche Médicale Several lines of evidence suggest that inflammation and oxidative stress could contribute to AD pathology (7,8). This may influence A␤ production to some extent, since BACE1 expression appears to be modulated by stress (9,10). Oxidative stress and inflammation are characterized by the release of cytokines and by reactive oxygen species, known to activate the nuclear factor-B (NF-B) (11,12).…”

Epigenetic mechanisms in Alzheimer's disease

“…There have been several reports of the activity, protein, and transcript levels of BACE1 being increased in AD (for reviews see Stockley and O'Neill 69 and Sun et al 70 ). Preclinical studies indicate that epigenetic mechanisms are involved in the increased expression of BACE1.…”

Sporadic inclusion-body myositis: A degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy

“…In addition, AβPP in s-IBM muscle fibers is posttranslationally modified, as evidenced by its increased phosphorylation [50]. Importantly, there are also distinct abnormalities in AβPP processing, including increased transcription and accumulation of BACE1 (β-site amyloid-β precursor protein cleaving enzyme) [26,51], which cleaves AβPP at the N-terminal of Aβ [52], and increased levels of BACE1-antisense (BACE1-AS) transcript [51], a non-coding RNA that regulates BACE1 mRNA and protein expression in vivo and in vitro, and was reportedly also increased in AD brains [53]. It would be of interest to study whether other non-coding RNAs are accumulated in s-IBM muscle fibers.…”

“…Impaired autophagy in s-IBM muscle fibers could be, at least partially, responsible for some of the abnormal accumulation of various proteins, including Aβ, α-syn, BACE1 and tau, all reported to be degraded through autophagy [52,91,100,101]. Of uncertain pathogenic significance, Aβ has been found to be produced within the autophagosomes [95,102].…”