Nanostring gene expression profiling for markers of Alzheimer's disease in MAPT P301S cTFEB HSACre and MAPT P301S male and female mice
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PROVIDER: PRJNA1076665 | ENA |
REPOSITORIES: ENA
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Project description:To assess the potential neuroprotective effects of overexpressing skeletal muscle Transcription Factor EB (TFEB) signaling in the context of age-associated neurodegenerative disease pathologies, we derived cTFEB;HSACre transgenic mice in the MAPT P301S tau hyperphosphorylated background and used the Nanostring nCounter® Alzheimer’s Disease panel to gain more precise insights into disease-relevant transcriptional changes in the hippocampus in both male and female mice with both Tau hyperphosphorylation and skeletal muscle TFEB overexpression. We confirmed significantly reduced transcriptional activation of the nCounter AD microglial activation module through signature scoring.
2024-02-14 | GSE242362 | GEO
Project description:The development of an effective therapy against tauopathies like Alzheimer’s disease (AD) and frontotemporal dementia (FTD) remains challenging, partly due to limited access to fresh brain tissue, the lack of translational in vitro disease models and the fact that underlying molecular pathways remain to be deciphered. Several genes play an important role in the pathogenesis of AD and FTD, one of them being the MAPT gene encoding the microtubule-associated protein tau. Over the past few years, it has been shown that induced pluripotent stem cells (iPSC) can be used to model various human disorders and can serve as translational in vitro tools. Therefore, we generated iPSC harboring the pathogenic FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) associated mutations IVS10+16 with and without P301S in MAPT using Zinc Finger Nuclease technology. Whole transcriptome analysis of MAPT IVS10+16 neurons reveals neuronal subtype differences, reduced neural progenitor proliferation potential and aberrant WNT signaling. Notably, all phenotypes were recapitulated using patient-derived neurons. Finally, an additional P301S mutation causes an increased calcium bursting frequency, reduced lysosomal acidity and tau oligomerization. Altogether, these tau mutant iPSC lines allow us to study IVS10+16 and P301S mutations in an isogenic background and to unravel a potential link between pathogenic 4R tau expression and FTDP-17.
2018-08-01 | GSE104013 | GEO
Project description:Alzheimer’s disease is known to alter astrocytes, but the effect of Aß and Tau pathology on these cells remains poorly understood. We investigated the transcriptomic behaviour of astrocytes (via translating ribosome affinity purification (TRAP)), and bulk brain tissue, in mouse models of APP/PS1 ß-amyloidopathy and MAPT-P301S tauopathy, in a mouse model overexpressing cytoprotective Nrf2 specifically in astrocytes (GFAP-Nrf2 model), and in crosses between the amyloidopathy and tauopathy models with the GFAP-Nrf2 mouse.
2021-12-02 | E-MTAB-10985 | biostudies-arrayexpress
Project description:Mapttm1(EGFP)Klt/J mice (Mapt-EGFP; The Jackson Laboratory, Bar Harbor, ME, USA; stock 004779) carry a knock-in of the EGFP coding sequence in the first exon of the microtubule-associated protein tau (Mapt) gene producing a cytoplasmic EGFP fused to the first 31 amino acids of MAPT. EGFP expression marks neurons including enteric neurons regardless of their lineage, closely patterning the expression of neuron-specific beta-tubulin III (TUBB3). Mapt-EGFP ice were backcrossed to C57BL/6J (Jackson Laboratory strain #:000664) for three to five generations at Mayo Clinic. Six male and six female Mapt-EGFP mice (54-98 days of age) underwent surgical laparotomy in 3 groups (surgery #1: 1 male and 1 female, surgery #2: 3 males and 1 female, surgery #3: 2 males and 4 females) under pentobarbital (50mg/kg) anesthesia. The celiac ganglion of each mouse was injected with 3-5 μL of 25 mg/mL Alexa Fluor 647-labeled cholera toxin subunit B (CTB-AF647; Thermo Fisher Scientific, Waltham, MA, USA) with the intention of labeling the cell soma of intestinofugal neurons in the myenteric plexus of the colon. The animals were killed 3-4 days after surgery. The muscularis externa of the colon from each Mapt-EGFP mouse was pooled together between all mice of the same surgery date (2, 4, and 6 mice) and mechanically and enzymatically dissociated into single cells with a two-step process that first enriches for cells within myenteric ganglia (PMCID: PMC8114175). The pooled cells from each group of mice formed one biological replicate and subjected to FACS immediately after dissociation to generate populations of Mapt-EGFP+ neurons with or without the CTB-AF647 tracer and Mapt-EGFP− non-neuronal cells. The frequency of Mapt-EGFP+CTB-AF647+ neurons was approximately 125-fold lower than that of Mapt-EGFP+CTB-AF647− neurons and RNA from these preparations did not pass quality control. Therefore, only data from Mapt-EGFP+CTB-AF647− neurons were analyzed and referred to as Mapt-EGFP+ cells. Total RNA was isolated from Mapt-EGFP+ colonic neurons and Mapt-EGFP− myenteric cells using RNA-Bee (AMSBIO, Cambridge, MA, USA) and purified with RNeasy Mini Kit (Qiagen, Germantown, MD, USA). RNA quality was tested using Agilent Electropherogram (Agilent Technologies, Santa Clara, CA, USA) and hybridized to Affymetrix Mouse Genome 430.2 gene expression microarrays (Thermo Fisher Scientific, Waltham, MA, USA). This study utilized Affymetrix Mouse Genome 430.2 oligonucleotide microarray analysis to charaterize the transcriptome of Mapt-EGFP+ neurons and Mapt-EGFP- non-neuronal myenteric cells isolated from the colon of Mapttm1(EGFP)Klt/J mice.
2024-02-14 | GSE199990 | GEO
Project description:ZFN engineered hiPSC with the FTDP-17 associated MAPT IVS10+16 mutation w/wo additional P301S mutation
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Project description:We looked to find earlier molecular changes in 2-month-old transgenic P301S mice. S-nitrosylated (SNO) proteins were identified in two brain regions, cortex and hippocampus, in P301S and Wild Type (WT) littermate control mice.
2019-11-08 | PXD010106 | Pride
Project description:Synapse loss and glial activation are hallmarks of Alzheimer's disease (AD). In Tau P301S transgenic mice, the complement pathway contributes to neuronal damage through microglial elimination of synapses. Here, we used unbiased proteomic profiling of postsynaptic density (PSD) fractions from Tau P301S mice in C1q-WT versus C1q knockout backgrounds to identify C1q-dependent changes at synapses. Integrative multi-omics analysis revealed that astrocyte- and microglia- specific proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. The same set of glial proteins (including C1q, C4, Gpnmb, and S100a4) is elevated in human AD synaptic fractions, and C4 levels are raised in cerebrospinal fluid (CSF) from AD patients. Besides microglia, we show that astrocytes contribute substantially to excitatory and inhibitory synapse engulfment in Tau P301S hippocampus. Based on staining of synapse markers within lysosomes, astrocytes showed preference for excitatory synapses whereas microglia preferred to engulf inhibitory synapse markers. Genetic deletion of C1q reduced astrocytic eating of excitatory and inhibitory synapses in Tau P301S mice, and rescued synapse density. Together, our data indicate that astrocytes contact and phagocytose synapses in a C1q- dependent manner and thereby contribute to synapse loss and neurodegeneration in AD.
2021-11-03 | MSV000088313 | MassIVE
Project description:The aim of this experiment was to assess the on- and off-target effects of MAPT-AS1 expression, and whether mutations/deletions to MAPT-AS1 alter these effects. SHSY5Y cells stably expressing variants of MAPT-AS1 were analyzed by Riboseq and Quantseq.
2021-03-20 | E-MTAB-9921 | biostudies-arrayexpress
Project description:Transcriptome analysis of Mapt-EGFP+ and Mapt-EGFP- myenteric cells
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Project description:We quantified genome-wide levels of H3K27ac in post-mortem entorhinal cortex tissue samples, identifying widespread Alzheimer's disease (AD)-associated acetylomic variation. Differentially acetylated peaks were identified in the vicinity genes implicated in both tau and amyloid neuropathology (MAPT, APP, PSEN1, PSEN2), as well as genomic regions containing variants associated with sporadic late-onset AD (CR1, TOMM40). Both MAPT and PSEN2 are characterized by an extended hyperacetylated region upstream of the TSS mapping to enhancers in the brain. We show that genes annotated to AD-associated hyper- and hypoacetylated peaks are enriched for brain- and neuropathology-related functions.
2018-08-11 | GSE102538 | GEO