RESUMEN
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease. It presents with progressive memory loss, worsens cognitive functions to the point of disability, and causes heavy socioeconomic burdens to patients, their families, and society as a whole. The underlying pathogenic mechanisms of AD are complex and may involve excitotoxicity, excessive generation of reactive oxygen species (ROS), aberrant cell cycle reentry, impaired mitochondrial function, and DNA damage. Up to now, there is no effective treatment available for AD, and it is therefore urgent to develop an effective therapeutic regimen for this devastating disease. Sestrin2, belonging to the sestrin family, can counteract oxidative stress, reduce activity of the mammalian/mechanistic target of rapamycin (mTOR), and improve cell survival. It may therefore play a crucial role in neurodegenerative diseases like AD. However, only limited studies of sestrin2 and AD have been conducted up to now. In this article, we discuss current experimental evidence to demonstrate the potential roles of sestrin2 in treating neurodegenerative diseases, focusing specifically on AD. Strategies for augmenting sestrin2 expression may strengthen neurons, adapting them to stressful conditions through counteracting oxidative stress, and may also adjust the autophagy process, these two effects together conferring neuronal resistance in cases of AD.
RESUMEN
Accumulation of senile plaques mainly composed of neurotoxic amyloid-beta peptide (Aß) is a pathological hallmark of Alzheimer's disease (AD). Sestrin2 inducible by various types of stressors is known to promote autophagy and exert antioxidative effects. In this work, we revealed the molecular mechanisms underlying Aß induction of sestrin2 and tested whether antioxidation, in addition to autophagy regulation, also contributes to its neuroprotective effects in primary rat cortical neurons. We found that Aß25-35 triggered nuclear translocation of p65 and p50, two subunits of nuclear factor-kappaB (NF-κB), and p53. Aß25-35-induced sestrin2 expression was abolished by the p65 siRNA, the NF-κB inhibitor SN50, and the p53 inhibitor pifithrin-alpha (PFT-α). Further, Aß25-35 enhanced binding of p50 and p53 to sestrin2 gene promoter that was abolished respectively by the p50 shRNA and PFT-α. Both p50 shRNA and PFT-α attenuated Aß25-35-induced expression as well as nuclear translocation of all three transcription factors, namely p65, p50, and p53. Interestingly, p50 binding to the promoters of its target genes required p53 activity, whereas p50 also negatively regulated p53 binding to its target sequences. Suppression of sestrin2 expression by siRNA enhanced Aß25-35- and Aß1-42-induced production of reactive oxygen species (ROS), lipid peroxidation, and formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG). In contrast, overexpression of the sestrin2 N-terminal or C-terminal fragments neutralized Aß25-35-induced ROS production. We concluded that Aß-induced sestrin2 contributing to antioxidant effects in neurons is in part mediated by p53 and NF-κB, which also mutually affect the expression of each other.
