Oxidative stress potentiates BACE1 gene expression and A? generation

Abstract

Alzheimer's Disease (AD) is the most common neurodegenerative disorder leading to dementia and its prevalence increases with age. The pathological features of AD are characterized by the beta-amyloid protein (A(beta)) deposits in the core of neuritic plaques and abnormal neurofibrillary tangles in the brain of AD patients. BACE1 is the major beta-secretase to cleave the beta-amyloid precursor protein (APP) to generate A(beta). Oxidative stress has been shown to affect A(beta) generation in the AD pathogenesis and the mechanism of such effect is unknown. In this report we generated a novel promoterless enhanced green fluorescent protein (EGFP) reporter gene cloning vector and cloned a 1.9-kb BACE1 gene promoter fragment in this vector. The BACE1 promoter fragment can efficiently activate EGFP or luciferase gene transcription. Oxidative stress induced by hydrogen peroxide resulted in significant increase in the BACE1 promoter activity. Furthermore, hydrogen peroxide treatment facilitated beta-secretase activity and A(beta) generation. Thus, upregulation of BACE1 transcription by oxidative stress may contribute to the pathogenesis of Alzheimer's disease.

Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1

“…Indeed, young adults carrying the ApoE4 allele, and MCI patients, exhibit reduced brain glucose metabolism (Reiman et al, 1996;Small et al, 2000;Mosconi et al, 2004;Mosconi, 2005), indicating that impaired energy metabolism may be an early contributing event to AD pathology rather than a consequence of the disease process. Importantly, several key down-stream cellular consequences of vascular insults and the resulting CBH, such as hypoxia, energy depletion and cellular stress have been linked with an elevation in BACE1 levels and activity (Tamagno et al, 2002(Tamagno et al, , 2005Tong et al, 2005;Velliquette et al, 2005;Sun et al, 2006;Xiong et al, 2007;Yan et al, 2007). Thus, in addition to potential elevations in Aβ occurring as a consequence of its own vasoactive properties, as detailed above, it appears possible that cardio-and cerebrovascular insults could elevate Aβ levels via a mechanism involving BACE1 elevation.…”

“…The identification of BACE1 substrates (for example, voltage-gated sodium channel β-subunit Na v 1β; neuregulin-1), in addition to APP, has begun to reveal potential BACE1 physiological functions (detailed below; Wang et al, 2005;Willem et al, 2006;Hu et al, 2006). Current indications are that BACE1 may function as a stress response protein that is upregulated in AD (Tamagno et al, 2002;Blasko et al, 2004;Wen et al, 2004;Tong et al, 2005;Velliquette et al, 2005;Tesco et al, 2007). Recent studies demonstrate that BACE1 levels are elevated in both AD experimental models and, importantly, in AD brain (Fukumoto et al, 2002;Holsinger et al, 2002;Tyler et al, 2002;Yang et al, 2003;Harada et al, 2006;Zhao et al, 2007).…”

“…Given the apparent importance of metabolic dysfunction and amyloidosis in AD, it is noteworthy that BACE1 upregulation has been observed under various experimental conditions likely involving energy disruption and/or mitochondrial stress (Tong et al, 2005;Velliquette et al, 2005;Sun et al, 2006;Tesco et al, 2007;Xiong et al, 2007). Indeed, elevated BACE1 levels and activity have been reported in vitro (Tamagno et al, 2002(Tamagno et al, , 2005Tong et al, 2005) and in vivo (Velliquette et al, 2005;Xiong et al, 2007) under conditions of altered energy metabolism and oxidative stress.…”

“…As is the case between Aβ and changes in the vasculature, Aβ accumulation may be both the cause and the consequence of oxidative stress. While Aβ accumulation can lead to oxidative stress (Tamagno et al, 2006), oxidative stress in vitro resulted in significant increases in BACE1 promoter activity (Tong et al, 2005) and following HNE exposure, an increase in BACE1 mRNA and protein levels, together with elevated Aβ production was observed (Tamagno et al, 2002(Tamagno et al, , 2005. Furthermore, the observation that oxidative stress upregulated BACE1 levels and the amyloidogenic processing of APP in smooth muscle cells led to the suggestion that this cell type may contribute to CAA observed in AD (Coma et al, in press).…”

Potential complementarity of high-flavanol cocoa powder and spirulina for health protection

“…[74][75][76] This is of considerable interest in light of evidence that oxidant stress generated by NADPH oxidase in activated microglia and possibly neurons as well plays an important pathogenic role in many common neurodegenerative disorders -including Alzheimers disease. [76][77][78][79][80][81][82] Indeed, oxidative stress up-regulates transcription of BACE1, an effect mediated by the stress-activated MAP kinases; [83][84][85][86][87][88] the resulting increase in amyloid-beta production then triggers further oxidative stress via activation of NAPDH oxidase, completing a feed-forward loop. [89][90][91][92][93][94] Oxidative stress also promotes transcription of presenilin-1, the catalytic component of the gamma-secretase also required for amyloid-beta production.…”