The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

Cissé, Moustapha Alfa; Duplan, Eric; Checler, Frédéric

doi:10.2119/molmed.2016.00229

Cited by 26 publications

(19 citation statements)

References 242 publications

(218 reference statements)

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“…During AD, the continuous accumulation of Aβ or p‐tau is proposed to result in abnormal levels of ER stress, contributing to synapse dysfunction and neurodegeneration . In the past 10 years, accumulating evidence supports a therapeutic potential of targeting the UPR to slow down AD in various preclinical models using pharmacological or gene therapy approaches . In this review, we discuss the latest discoveries highlighting the functional role of ER stress in AD and its impact in synaptic dysfunction and cognitive impairment.…”

Section: Introductionmentioning

confidence: 98%

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

2017

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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synaptic dysfunction and accumulation of abnormal aggregates formed by amyloid-β peptides or phosphorylated tau proteins. Accumulating evidence suggests that alterations in the buffering capacity of the proteostasis network are a salient feature of AD. The endoplasmic reticulum (ER) is the main compartment involved in protein folding and secretion and is drastically affected in AD neurons. ER stress triggers the activation of the unfolded protein response (UPR), a signal transduction pathway that enforces adaptive programs to recover homeostasis or trigger apoptosis of irreversibly damaged cells. Experimental manipulation of specific UPR signaling modules in preclinical models of AD has revealed a key role of this pathway in regulating protein misfolding and neurodegeneration. Recent studies suggest that the UPR also influences synaptic plasticity and memory through ER stress-independent mechanisms. Consequently, targeting of the UPR in AD is emerging as an interesting therapeutic approach to modify the two pillars of AD, protein misfolding and synaptic failure. Here, we review the functional role of ER stress signaling in AD, discussing the complex involvement of the pathway in controlling neuronal survival, the amyloid cascade, neurodegeneration and synaptic function. Recent intervention efforts to target the UPR with pharmacological and gene therapy strategies are also discussed.

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Section: Introductionmentioning

confidence: 98%

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

2017

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“…However, under chronic or irreversible ER stress conditions, the UPR shifts its signaling toward cell death 11 . Modulation of ER-UPR has therefore been one potential therapeutic strategy for slowing down AD, using gene therapy or pharmacological approaches 12,13 .…”

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confidence: 99%

FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism

Chen

Hao

et al. 2020

Nat Commun

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Alzheimer's disease (AD) is defined by progressive neurodegeneration, with oligomerization and aggregation of amyloid-β peptides (Aβ) playing a pivotal role in its pathogenesis. In recent years, the yeast Saccharomyces cerevisiae has been successfully used to clarify the roles of different human proteins involved in neurodegeneration. Here, we report a genome-wide synthetic genetic interaction array to identify toxicity modifiers of Aβ42, using yeast as the model organism. We find that FMN1, the gene encoding riboflavin kinase, and its metabolic product flavin mononucleotide (FMN) reduce Aβ42 toxicity. Classic experimental analyses combined with RNAseq show the effects of FMN supplementation to include reducing misfolded protein load, altering cellular metabolism, increasing NADH/(NADH + NAD +) and NADPH/(NADPH + NADP +) ratios and increasing resistance to oxidative stress. Additionally, FMN supplementation modifies Htt103QP toxicity and α-synuclein toxicity in the humanized yeast. Our findings offer insights for reducing cytotoxicity of Aβ42, and potentially other misfolded proteins, via FMN-dependent cellular pathways.

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“…XBP1 occupancy was observed on the promoters of genes linked to neurodegenerative pathologies including Alzheimers disease [50], although the relevance of these events remains speculative. Indeed, XBP1 activates a plethora of target genes involved in a variety of physiological functions, including neuronal plasticity [51][50] [52], suggesting an important role during the branching and maturation of developing neurons. Accumulation of unfolded or misfolded proteins in the ER leads to an ER stress response, which is characteristic of cells with a high level of secretory activity and is implicated in a variety of disease conditions such as AD [53].…”

Section: Discussionmentioning

confidence: 99%

“…miRNAs play important roles in gene regulation and there is emerging evidence demonstrating their potential for use as biomarkers for AD and other diseases; it is likely therefore that miRNAs play significant roles in the pathogenic process underlying AD [55] [56]. Indeed, such roles have been suggested for miR-518e and miR-518a-3p in AD [51]. Similarly, miR-518c may also be a useful biomarker for Parkinson's disease [57] while miR-518b is dysregulated in esophageal carcinoma [58].…”

Section: Discussionmentioning

confidence: 99%

Identification of common molecular biomarker signatures in blood and brain of Alzheimer’s disease

Rahman¹,

Islam

Shahjaman

et al. 2018

Preprint

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Background: Alzheimers disease (AD) is a progressive neurodegenerative disease characterized by memory loss and confusion. Neuroimaging and cerebrospinal fluid-based early detection is limited in sensitivity and specificity as well as by cost. Therefore, detecting AD from blood cell analysis could improve early diagnosis and treatment of the disease. The present study aimed to identify blood cell transcripts that reflect brain expression levels of factors linked to AD progression. Methods: We analyzed blood cell and brain microarray gene expression datasets from NCBI-GEO for AD association and expression in blood and brain. We also used eQTL and epigenetics data to identify AD-related genes that were regulated similarly in blood and brain. Results: We identified 9 differentially expressed genes (DEG; AD versus controls) common to blood cells and brain (CNBD1, SUCLG2-AS1, CCDC65, PDE4D, MTMR1, C3, SLC6A15, LINC01806, and FRG1JP) and 18 genes (HSD17B1, GAS5, RPS5, VKORC1, GLE1, WDR1, RPL12, MORN1, RAD52, SDR39U1, NPHP4, MT1E, SORD, LINC00638, MCM3AP-AS1, GSDMD, RPS9, and GNL2) that were commonly dysregulated between AD blood and brain tissues using SNP and cis-eQTL data. This data revealed significant neurodegeneration-associated molecular pathways in the ribosomal and complement systems. Integration of these different analyses revealed dysregulation of hub transcription factors (SREBF2, NR1H2, NR1H3, PRDM1, XBP1) and microRNAs (miR-518e, miR-518a-3p, miR-518b, miR-518c, miR-518d-3p and miR-518f) in AD. Several significant histone modification sites in DEGs were also identified. Conclusion: We have identified new putative links between pathological processes in brain and transcripts in blood cells in AD subjects that may enable the use of blood to diagnose and monitor AD onset and progression.

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The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

Cited by 26 publications

References 242 publications

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism

Identification of common molecular biomarker signatures in blood and brain of Alzheimer’s disease

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