Abstract
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.
Highlights
We further demonstrated that Aβ-induced sestrin2 expression contributes to antioxidative activity in neurons; Aβ induction of sestrin2 is at least partly mediated by the activation of transcription factors nuclear factorκB (NF-κB) and p53 [40]
Upstream of p53 and NF-κB, we identified at least two signaling pathways, namely nitric oxide synthase/cyclic guanosine monophosphate (cGMP)-dependent protein kinase (NOS/PKG) and phosphatidylinositol 3-kinase (PI3K)/Akt, that may have contributed to the observed Aβ induction of sestrin2 in cortical neurons [40]
We have shown before that brain-derived neurotrophic factor (BDNF) can induce sestrin2 expression in rat primary cortical neurons and exert a protective effect against 3-Nitropropionic acid (3-NP) neurotoxicity by neuroblastoma cells; co-treatment of atorvastatin and Aβ reduced oxidative stress and decreased sestrin2 expression [103]
Summary
The extracellular senile plaques, the extracellular and intraneuronal Aβ oligomers, as well as tau oligomers and NFTs, together lead to excessive production of reactive oxygen species (ROS), Ca2+ overload, mitochondrial dysfunction, and disrupted energy homeostasis, causing neuronal death. In addition to those pictured above, other pathogenic mechanisms are not demonstrated in this figure due to limited space. We showed that sestrin functions as an endogenous protective mediator against Aβ-induced neurotoxicity, in part through enhancement of autophagy activity [39] In another recent study, we further demonstrated that Aβ-induced sestrin expression contributes to antioxidative activity in neurons; Aβ induction of sestrin is at least partly mediated by the activation of transcription factors NF-κB and p53 [40]. Finding the way to augmenting sestrin expression may have significant clinical implications, especially in treating many devastating neurodegenerative diseases, including AD
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