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Abstract
The initiation of protein synthesis is suppressed under several stress conditions, inducing phosphorylation of the α-subunit of the eukaryotic initiation factor 2 (eIF2α), thereby inactivating the GTP-GDP recycling protein eIF2B. By contrast, the mammalian activating transcription factor 4 (ATF4, also known as cAMP response element binding protein 2 (CREB2)) is still translated under stress conditions. Four protein kinases (general control nonderepressible-2 (GCN2) kinase, double-stranded RNA-activated protein kinase (PKR), PKR-endoplasmic reticulum (ER)-related kinase (PERK), and heme-regulated inhibitor kinase (HRI)) phosphorylate eIF2α in the presence of stressors such as amino acid starvation, viral infection, ER stress, and heme deficiency. This signaling reaction is known as the integrated stress response (ISR). Here, we review ISR signaling in the brain in a mouse model of Alzheimer’s disease (AD). We propose that targeting ISR signaling with quercetin has therapeutic potential, because it suppresses amyloid-β (Aβ) production in vitro and prevents cognitive impairments in a mouse model of AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder with increasing prevalence worldwide, and characterized by the deposition of neurofibrillary tangles and amyloid in the brain
Several reviews have indicated that α-subunit of the eukaryotic initiation factor 2-mediated translational control regulates synaptic plasticity [7], that eIF2α phosphorylation is a molecular link between AD and diabetes [6], and that the integrated stress response (ISR) mediates memory impairments in AD associated with apolipoprotein E ε4 (ApoE4) [8]
This study demonstrated that gene transcription in the hippocampus is enhanced in General control nonderepressible-2 (GCN2)−/− mice because cAMP response element binding protein 2 (CREB)-targeting gene expression is increased when ATF4 expression is downregulated
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder with increasing prevalence worldwide, and characterized by the deposition of neurofibrillary tangles and amyloid in the brain. These changes may affect memory and other cognitive functions [1]. Quercetin can improve several pathological conditions such as diabetes [10] and AD through regulation of anti-oxidative stress enzymes via the action of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the antioxidant effect of paraoxonase 2 (PON2) expression [11,12]. Several studies suggest the effects of quercetin on memory and cognition improvement may be associated with ISR regulation [14,15,16]. We discuss ISR signaling in AD and the effects of quercetin on memory and adult neurogenesis
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