Alterations in cholesterol metabolism–related genes in sporadic Alzheimer's disease

Picard, Cynthia; Julien, Cédric; Frappier, Josée; Miron, Justin; Théroux, Louise; Dea, Doris; Breitner, John C.S.; Poirier, Judes

doi:10.1016/j.neurobiolaging.2018.01.018

Cited by 49 publications

(37 citation statements)

References 51 publications

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“…However, this was not supported in vivo where increased cholesterol synthesis and mitochondrial cholesterol influx along with increased mSREBP‐2 was found in APP/PS1 mice . Most recently, one SREBP‐2 polymorphism rs2269657 showed significant associations with LOAD pathological biomarkers . To better understand the abnormal cholesterol metabolism in AD, it is important to understand whether and how the expression and activation of SREBP‐2 is changed in AD, which is the main focus of this study.…”

Section: Introductionmentioning

confidence: 93%

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

et al. 2019

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Disturbed neuronal cholesterol homeostasis has been observed in Alzheimer disease (AD) and contributes to the pathogenesis of AD. As the master switch of cholesterol biosynthesis, the sterol regulatory element-binding protein 2 (SREBP-2) translocates to the nucleus after cleavage/activation, but its expression and activation have not been studied in AD which is the focus of the current study. We found both a significant decrease in the nuclear translocation of N-terminal SREBP-2 accompanied by a significant accumulation of C-terminal SREBP-2 in NFT-containing pyramidal neurons in AD. N-terminal-SREBP-2 is also found in dystrophic neurites around plaques in AD brain. Western blot confirmed a significantly reduced nuclear translocation of mature SREBP-2 (mSREBP-2) in AD brain. Interestingly, reduced nuclear mSREBP-2 was only found in animal models of tauopathies such as 3XTg AD mice and P301L Tau Tg mice but not in CRND8 APP transgenic mice, suggesting that tau alterations likely are involved in the changes of mSREBP-2 distribution and activation in AD. Altogether, our study demonstrated disturbed SREBP-2 signaling in AD and related models, and proved for the first time that tau alterations contribute to disturbed cholesterol homeostasis in AD likely through modulation of nuclear mSREBP-2 translocation.

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Section: Introductionmentioning

confidence: 93%

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

et al. 2019

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“…SREBF2: The SREBF2 is a cholesterol regulating genes and significant increased mRNA levels expressesion were observed in the late onset AD in brain and blood microarray observations suggesting SREBF as biomarkers of AD at pathogolical and gene expression levels Picard et al [37]. In another study evaluated the SREBF2 mRNA level expression in neurodegenerative prion disease.…”

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 LDLR gene encodes the LDL receptor, one of the neuronal receptors capable of mediating the endocytosis of ApoE and, thus, maintaining brain cholesterol homeostasis. LDLR expression is regulated, in part, by SREBF2 , a transcriptional regulator of sterol-regulated genes, which contains a SNP that is associated both with SREBF2 expression and CSF levels of the AD biomarkers Aβ and tau [42]. SQLE encodes squalene monooxygenase, a rate-limiting catalyst in sterol biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2

Martin

Vaher

Bermingham

et al. 2019

Preprint

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INTRODUCTIONThe Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD), while the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers but associations with epigenome-wide methylation are unknown.METHODSThe EPIC array was used to identify methylation differences between AD-free APOE ε4 (n=2469) and ε2 (n=1108) carriers using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and meQTL analyses.RESULTSDifferentially methylated positions were identified in APOE, surrounding genes and genes outside of this locus (DHCR24, LDLR and ABCG1). DMRs were identified in SREBF2, LDLR and SQLE. Pathway and meQTL analyses implicated lipid-related processes; however, blood cholesterol levels could not fully account for the associations.DISCUSSIONAPOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in cis and trans in genes involved in lipid homeostasis.

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Alterations in cholesterol metabolism–related genes in sporadic Alzheimer's disease

Cited by 49 publications

References 51 publications

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

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

Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2

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