Relative Alterations in Blood-Based Levels of Sestrin in Alzheimer’s Disease and Mild Cognitive Impairment Patients

Rai, Nitish; Kumar, Rahul; Desai, Gaurav; Venugopalan, G.; Shekhar, Shashank; Chatterjee, Prasun; Tripathi, Manjari; Upadhyay, Ashish Datt; Dwivedi, Sadanand; Dey, Aparajit Ballav

doi:10.3233/jad-160479

Cited by 27 publications

(24 citation statements)

References 31 publications

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“…Peripheral blood biomarkers for early diagnosis have been examined in many diseases including AD [40][41][42]. In addition, various blood biomarkers associated with neurocognitive impairments have been reported, for example, glucose [43][44][45] and atherogenic index of plasma (AIP) [46].…”

Section: Discussionmentioning

confidence: 99%

Identification of potential blood biomarkers for early diagnosis of Alzheimer’s disease through RNA sequencing analysis

et al. 2020

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Background: With demographic shifts toward older populations, the number of people with dementia is steadily increasing. Alzheimer's disease (AD) is the most common cause of dementia, and no curative treatment is available. The current best strategy is to delay disease progression and to practice early intervention to reduce the number of patients that ultimately develop AD. Therefore, promising novel biomarkers for early diagnosis are urgently required. Methods: To identify blood-based biomarkers for early diagnosis of AD, we performed RNA sequencing (RNA-seq) analysis of 610 blood samples, representing 271 patients with AD, 91 cognitively normal (CN) adults, and 248 subjects with mild cognitive impairment (MCI). We first estimated cell-type proportions among AD, MCI, and CN samples from the bulk RNA-seq data using CIBERSORT and then examined the differentially expressed genes (DEGs) between AD and CN samples. To gain further insight into the biological functions of the DEGs, we performed gene set enrichment analysis (GSEA) and network-based meta-analysis. Results: In the cell-type distribution analysis, we found a significant association between the proportion of neutrophils and AD prognosis at a false discovery rate (FDR) < 0.05. Furthermore, a similar trend emerged in the results of routine blood tests from a large number of samples (n = 3,099: AD, 1,605; MCI, 994; CN, 500). In addition, GSEA and network-based meta-analysis based on DEGs between AD and CN samples revealed functional modules and important hub genes associated with the pathogenesis of AD. The risk prediction model constructed by using the proportion of neutrophils and the most important hub genes (EEF2 and RPL7) achieved a high AUC of 0.878 in a validation cohort; when further applied to a prospective cohort, the model achieved a high accuracy of 0.727. Conclusions: Our model was demonstrated to be effective in prospective AD risk prediction. These findings indicate the discovery of potential biomarkers for early diagnosis of AD, and their further improvement may lead to future practical clinical use.

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Section: Discussionmentioning

confidence: 99%

Identification of potential blood biomarkers for early diagnosis of Alzheimer’s disease through RNA sequencing analysis

et al. 2020

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“…Sesn2 is a critical factor mediating reactive oxygen species formation, in part by inhibiting AMPK pathway member mTORC1 (Ebnoether, Ramseier, Cortada, Bodmer, & Levano-Huaman, 2017). Sesn2 is also induced by Ab exposure in vitro and upregulated in serum of AD patients (Chen, Chen, Wu, Huang, & Yang, 2014;Rai et al, 2016). Therefore, normalization of the AMPK cascade and/or downstream signaling pathway members, as seen with MCS, may be considered therapeutic targets in DS and AD.…”

Section: Cellular Homeostasis Regulationmentioning

confidence: 99%

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

et al. 2018

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Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a therapeutic intervention, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aβ) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.

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“…Chen et al demonstrated that Sesn2 is induced by amyloid β-peptide, which is a biomarker of Alzheimer’s disease, and protects cortical neurons against amyloid β-peptide by regulating autophagy [58]. In addition, clinical study showed that the serum levels of Sesn2 were significantly increased in the Alzheimer’s disease group compared to mild cognitive impairment, and elderly controls [59]. Another study indicated that Sesn2 is upregulated in the midbrains from Parkinson’s disease patients [60].…”

Section: Sesns In the Nervous Systemmentioning

confidence: 99%

Recent Insights into the Biological Functions of Sestrins in Health and Disease

Wang

Liu

et al. 2017

Cell Physiol Biochem

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Sestrins (Sesns) have been identified as a family of highly conserved stress-inducible proteins that are strongly up-regulated by various stresses, including DNA damage, oxidative stress, and hypoxia. The Sesns play protective roles in most physiological and pathological conditions mainly through the regulation of oxidative stress, inflammation, autophagy, endoplasmic reticulum stress, and metabolic homeostasis. In this review, we discussed the possible regulators of Sesns expression, such as p53, forkhead box O, nuclear factor erythroid 2 like 2 (Nrf2), NH (2)-terminal kinase (JNK)/c-Jun pathway and hypoxia-inducible factor-1α (Hif-1α), and the downstream pathways regulated by the Sesns including AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, mitogen-activated protein kinases (MAPKs) signaling, Nrf2 signaling, NADPH oxidase signaling and transforming growth factor β (TGF-β) signaling in heart diseases, lung diseases, gastrointestinal tract diseases, liver and metabolism diseases, neurological diseases, kidney diseases and immunological diseases. This review aims to provide a comprehensive understanding the protective effects of Sesns.

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Relative Alterations in Blood-Based Levels of Sestrin in Alzheimer’s Disease and Mild Cognitive Impairment Patients

Cited by 27 publications

References 31 publications

Identification of potential blood biomarkers for early diagnosis of Alzheimer’s disease through RNA sequencing analysis

Identification of potential blood biomarkers for early diagnosis of Alzheimer’s disease through RNA sequencing analysis

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

Recent Insights into the Biological Functions of Sestrins in Health and Disease

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