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SCD inhibition reverses immune, synaptic and behavioral deficits in an animal model of Alzheimer’s disease [scRNA-Seq]

ABSTRACT: Early- and late-onset forms of Alzheimer’s disease (AD) share common features that include abnormalities in lipid metabolism, immune response and synaptic function. Of these, the role of lipids remains the least understood. Our study revealed that molecular functions related to Stearoyl-CoA Desaturase (SCD), the rate limiting enzyme in monounsaturated fatty acid synthesis were specifically altered in the hippocampus of 3xTg-AD (a model of early-onset AD). Remarkably, infusion of an SCD inhibitor (SCDi) reversed 40% of altered immune and synapse genes, rescue dendritic spine number and structure, recovered activity-associated immediate-early gene expression and restored learning and memory in 3xTg-AD mice. In addition, we employed single cell RNA sequencing to characterize the cellular landscape of microglia subpopulations within the 3xTg hippocampus and uncovered that SCDi reversed microglial activation and polarization. Together, we show that a single lipid enzyme, SCD, impinges on the core features of AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE167600 | GEO | 2022/02/25

REPOSITORIES: GEO

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SCD inhibition reverses immune, synaptic and behavioral deficits in an animal model of Alzheimer’s disease [bulk RNA-Seq]

Project description:Early- and late-onset forms of Alzheimer’s disease (AD) share common features that include abnormalities in lipid metabolism, immune response and synaptic function. Of these, the role of lipids remains the least understood. Our study revealed that molecular functions related to Stearoyl-CoA Desaturase (SCD), the rate limiting enzyme in monounsaturated fatty acid synthesis were specifically altered in the hippocampus of 3xTg-AD (a model of early-onset AD). Remarkably, infusion of an SCD inhibitor (SCDi) reversed 40% of altered immune and synapse genes, rescue dendritic spine number and structure, recovered activity-associated immediate-early gene expression and restored learning and memory in 3xTg-AD mice. In addition, we employed single cell RNA sequencing to characterize the cellular landscape of microglia subpopulations within the 3xTg hippocampus and uncovered that SCDi reversed microglial activation and polarization. Together, we show that a single lipid enzyme, SCD, impinges on the core features of AD.

2022-02-25 | GSE167601 | GEO

Misprocessing of APP and accumulation of β-Amyloid causes early alteration of pathways implicated in late-onset Alzheimer disease.

Project description:Genome-wide association studies (GWAS) have identified genes in lipid metabolism,inflammation and vesicular trafficking pathways as risk factors for late onset Alzheimer disease (LOAD). The mechanism by which they cause AD and their relationship to the amyloid cascade affected by genes causing early onset familial AD is unknown. Unproven hypotheses are that these LOAD genes modulate the amyloid cascade itself or downstream targets affected by this cascade.If so, it is likely that these genes and/or other genes in the same pathways may show alterations in their expression as an early consequence of misprocessing of amyloid precursor protein (APP) and accumulation of amyloid β-peptides (Aβ). We report that in three independent APP transgenic mouse models of AD, multiple genes in lipid and inflammation pathways show very early changes in mRNA and protein expression. Many of these changes are reversed by treatment with LXR agonists, which regulate transcription of genes in lipid/inflammation pathways, and which we have previously shown can reverse the cognitive deficits and neuropathology in Tg2756 mice. These results suggest that changes in lipid and inflammation pathways are likely to be very early consequences of APP misprocessing and Aβ accumulation in AD. Moreover, genetic variants within these pathways might affect risk for AD by modulating this early response. These pathways are likely to contain biomarkers of early disease and targets for therapies. TgCRND8 mice and wild-type littermate controls at ages 70, 80, and 150 days (n = 4 mice per cohort) were used in the study.

2014-08-12 | E-GEOD-31372 | biostudies-arrayexpress

Expression data from Alzheimer's disease model mouse

Project description:To identify molecular pathological alterations in AD brains, we performed interspecies comparative microarray analyses using RNAs prepared from postmortem human brain tissues donated for the Hisayama study and hippocampal RNAs from the triple-transgenic mouse model of AD (3xTg-AD) Three-way ANOVA of microarray data from frontal cortex, temporal cortex and hippocampus with presence/absence of AD and vascular dementia, and sex, as factors revealed that the gene expression profile is most significantly altered in the hippocampi of AD brains. Comparative analyses of the brains of AD patients and a mouse model of AD showed that genes involved in non-insulin dependent DM and obesity were significantly altered in both, as were genes related to psychiatric disorders and AlzheimerM-bM-^@M-^Ys disease. 3xTg-AD-H mice harboring a homozygous Psen1M146V mutation and homozygous mutant transgenes for APPSwe and tauP301L, 3xTg-AD-h mice harboring hemizygous APPSwe and tauP301L transgenes with a homozygous Psen1M146V mutation, and non-transgenic control mice (non-Tg) were used in this study, (male, n=3 for each group). RNA samples prepared from hippocampi were subjected to microarray analysis using the Affymetrix Mouse Gene 1.0 ST platform (GPL6246).

2013-04-17 | E-GEOD-36981 | biostudies-arrayexpress

Misprocessing of APP and accumulation of β-Amyloid causes early alteration of pathways implicated in late-onset Alzheimer disease.

2014-08-12 | GSE31372 | GEO

microRNA-132/212 deficiency enhances Ab production and senile plaque deposition in Alzheimerâs disease triple transgenic mice

Project description:The abnormal regulation of amyloid-b (Ab) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimerâs disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Ab deposition and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Ab metabolism, including Tau, Mapk, and Sirt1. We used RNA-Seq to analyse the hippocampus of 3xTg-AD mice lacking the miR-132/212 cluster as well as Neuro2a cells overexpressing miR-132 mimics.

2016-07-17 | E-GEOD-84481 | biostudies-arrayexpress

Early-onset pediatric atopic dermatitis is characterized by Th2/Th17/Th22- centered inflammation and lipid alterations

Project description:Background: While atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early-onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need of better treatments. Objective: We sought to globally profile the skin of infants with AD compared to adults with AD and healthy controls. Methods: We performed microarray, RT-PCR and fluorescence microscopy studies in infants and young children (<5yo) with early-onset AD (<6mo) compared to age-matched controls and adults with longstanding AD. Results: Transcriptomic analyses revealed profound differences between early-onset pediatric vs. longstanding adult AD, not only in lesional but also non-lesional tissues. While both patient populations harbored Th2-centered inflammation, pediatric AD also showed significant Th17-skewing, but lacked the Th1 upregulation that characterizes adult AD. Defects in lipid barrier (e.g. ELOVL3, DGAT2) and tight junction regulation (e.g. Claudins 8 and 23) were evident in both groups but, unlike adult AD which showed the classic downregulation of epidermal differentiation and cornification products, pediatric AD exhibited relatively normal expression of these genes. Some lipid-associated mediators (such as FAR2 and FA2H) even showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H, DGAT2) showed inverse correlations with transepidermal water loss/TEWL, a functional measure of the epidermal barrier. Conclusions: Children and adult AD skin samples share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease.

2018-05-21 | GSE107361 | GEO

Transcriptomes of Neural Stem and Progenitor Cells from the subgranular zone (SGZ) of Wild Type (NTG) and 3xTg-AD mice at juvenile age

Project description:The goals of this study are to compare transcriptome profiling (RNA-seq) in wild-type (NTG) and 3xTg-AD mice, to determine the transcriptomal changes of neural stem and progenitor cells (NSPC) from the SGZ at early stages of Alzheimer's Disease in a mouse model. Methods: A tamoxifen (TAM)-inducible Nestin-CreERT2;ROSA26-EYFP reporter mouse line was cross-bred with NTG or 3xTG-AD mice to label NSPC upon TAM administration. YFP-positive NSPCs were sorted through FACS (Fluorescence-Activated Cell Sorting) 10 days after TAM from NTG; Nestin-CreERT2;ROSA26-EYFP and 3xTg-AD;Nestin-CreERT2;ROSA26-EYFP mice. RNA was extracted with RNeasy Micro Kit and deep-sequenced on the NovaSeq SP flowcell SR200 platform. The sequence reads of Fastq files that passed quality filters were aligned to the mouse genome (build mm10) using hisat2. Samtools was used to index the BAM files. DESeq2 was used to establish differential gene expression between NTG and 3xTg-AD samples. Results: We mapped about 48 million sequence reads per sample to the mouse genome (build mm10) and identified 1391 genes that were differentially expressed in the 3xTg-AD, with 720 down- and 671 up-regulated. Genes were considered significantly different between two genotypes if they meet the following criteria: 1) adjusted p-value < 0.05, and 2) log2 fold change > 0.5 or < -0.5. Conclusions: Gene ontology analysis of differentially expressed genes uncovered several pathways that may contribute to early neural stem cell decline in the 3xTg mice. Our results revealed very early perturbations in the SGZ neurogenic niche in the 3xTg mouse model of AD, manifested by intrinsic molecular changes in neural stem and progenitor cells (NSPC) at juvenile age, resulting in dysregulated neural stem cell homeostasis.

2023-02-15 | GSE218323 | GEO

Whole Blood Transcriptome Characterization of 3xTg-AD Mouse and its modulation by transcranial Direct Current Stimulation (tDCS)

Project description:The 3xTg-AD mouse is a widely used model in the study of Alzheimer’s Disease (AD). It has been extensively characterized both from the anatomical and behavioral point of view but poorly studied at the transcriptomic level. For the first time, this study characterizes the whole blood transcriptome of the 3xTg-AD mouse at three and six months of age and evaluates how gene expression is modulated by transcranial direct current stimulation (tDCS). RNA-seq analysis revealed 183 differentially expressed genes (DEGs) that were a direct signature of the genetic background of the mouse. The expression profile of age-related genes in the 3 months-old 3xTg-AD mice was more similar to that of 6 months rather than 3 months-control mice, suggesting a premature aging of the 3xTg-AD mice. Moreover, in the 6 months-old 3xTg-AD mice, we observed a high number of DEGs that could represent good peripheral biomarkers of AD progression. Finally, tDCS was associated with gene expression changes in the 3xTg-AD but not in the control mice. In conclusion, this study provides a better molecular characterization of the 3xTg-AD mouse and suggests that blood gene expression can be used to identify new biomarkers of AD progression and treatments effect.

2021-07-19 | GSE178662 | GEO

Comprehensive evaluation of Ubiquinol-supplemented diet effects in the 3xTg AD mice using MALDI-MSI

Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disorder, accounting for up to 75 % of all dementia cases. Although the basis of AD etiology remains unknown, oxidative stress constitutes a major driver given its intimate association, specially at prodromic stages of the disease. In this line, Ubiquinol, the reduced form of coenzyme Q10, is a well-known neuroprotective antioxidant and has demonstrated significant effects in oxidative responses of β-Amyloid aggregation, internalization, and apoptosis-induced neurodegeneration. However, full extent of Ubiquinol effects in the context of AD is not yet known in detail. In this study, we designed a new methodology based on MALDI MSI for evaluating the peptide profile of the 3xTg-AD mice model fed a Ubiquinol-supplemented diet. By adopting functional analysis tools, we observed differential functional profile in hippocampus and cortex levels after 4- or 10-m o supplementation. Therefore, we also identified ACAD9, XPO1 and EIF3A as potential protein references for the diagnosis of AD at early/late stages.

2023-05-10 | PXD037763 | Pride

Lateral ventricle SVZ: 3xTg vs WT

Project description:Transcriptional profiling of the microdissected SVZ from 7-month-old mice Adult neurogenesis is suppressed in the SVZ of 3xTg mice, a model of Alzheimer's disease. To better understand the underlying mechanisms of this suppression, the goals of this experiment were to compare the transcriptional profiles of the SVZ neural stem cell niche in 3xTg-AD mice versus strain controls. We used early middle-aged mice (7-months-old) rather than old mice, in order to identify genetic changes that are not caused secondarily to other degenerative changes occurring in these mice. Two-condition experiment, 3xTg vs WT SVZ. Biological replicates: 4 for each.

2015-08-01 | E-GEOD-60460 | biostudies-arrayexpress

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