The up‐regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1α

Abstract

While it is well established that stroke and cerebral hypoperfusion are both significant risk factors for Alzheimer’s disease, the molecular link between ischemia and amyloid precursor protein processing has only been recently established. Specifically, hypoxia significantly increases β‐site APP cleaving enzyme (BACE1) gene transcription through the over‐expression of hypoxia inducible factor 1α, resulting in increased BACE1 secretase activity and amyloid‐β production. In this study, we significantly extend these findings both in vitro, in differentiated SK‐N‐BE neuroblastoma cells, and in vivo, in rats subjected to cerebral ischemia, showing that hypoxia up‐regulates BACE1 expression through a biphasic mechanism. The early post‐hypoxic up‐regulation of BACE1 depends on the production of reactive oxygen species mediated by the sudden interruption of the mitochondrial electron transport chain, while the later expression of BACE1 is caused by hypoxia inducible factor 1α activation. The involvement of reactive oxygen species released by mitochondria in the BACE1 up‐regulation was confirmed by the complete protection exerted by complex I inhibitors such as rotenone and diphenyl‐phenylen iodonium. Moreover, the oxidative stress‐mediated up‐regulation of BACE1 is mediated by c‐jun N terminal kinase pathway as demonstrated by the protection exerted by the silencing of c‐jun N‐terminal kinase isoforms 1 and 2. Our study strengthens the hypothesis that oxidative stress is a basic common mechanism of amyloid‐β accumulation.

The Mitochondrial Secret(ase) of Alzheimer's Disease

“…On one hand, oxidative stress leads to downstream increases in Aβ-producing enzyme activity, specifically through increased BACE1 activity and presenilin 1 levels [166,167]. On the other hand, the presence of Aβ leads to increased generation of ROS, therefore puzzling researchers with the question of which pathology arose first in cases of sporadic AD.…”

“…First, increased BACE protein levels and activity in postmortem AD brain [54,162] are linked to increased γ-secretase cleavage of AβPP [163] and correlate with oxidative stress levels [164]. Endogenously and exogenously-induced ROS overproduction increases both BACE1 and PS1 expression and activity [165][166][167][168], which are mediated through the activation of the JNK pathway [169][170][171] and results in increased Aβ production [161,172]. In addition, Jo and colleagues report γ-secretase is responsible for ROS-induced increases in β-secretase activity, since pharmacological or genetic loss of γ-secretase function ameliorates an increase in β-secretase [173].…”

Enhancement of β-secretase inhibition and antioxidant activities oftempeh, a fermented soybean cake through enrichment of bioactive aglycones

“…Since the main culprit of Ab aggregation is the b-secretase (BACE1), the inhibition of this enzyme is believed to play an important role in the prevention of AD (Tresadern et al, 2011). Oxidative stress has been found to elevate BACE1 levels in cultured neurons and animal models (Guglielmotto et al, 2009).…”

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

“…Повторные гипоксии-ишемии приводят к концентрированию пуриновых производных (адено-зин и гипоксантин), которые усиливают повреждение нейронов при реоксигенации [64]. Активация оксидаз и синтазы оксида азота (Nitric oxide synthase, NOS), повы-шение регуляции индуцируемого гипоксией фактора HIF-1␣, а также снижение экспрессии антиоксидантных ферментов, таких как супероксиддисмутаза, каталаза и глутатионпероксидаза, генерируют взрыв реактивного кислорода (Reactive oxygen species, ROS) на реоксиге-нацию [65]. Дополнительно к этому NOS и оксид азота образуют сильный окислитель -пероксинитрит [66].…”