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.
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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:Spatial transcriptome sequencing technology has provided high-resolution transcriptome data for studying the molecular mechanism of Tau P301S mediating Alzheimer's disease-like pathological changes in zebrafish, providing a unique insight into the pathogenesis of tau pathology-mediated cell-cell interactions in AD.
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Project description:Tau neurofibrillary tangles are a hallmark of several neurodegenerative diseases called tauopathies, including frontotemporal dementia and Alzheimer's Disease. Ongoing clinical trials for tauopathies seek to reduce Tau in the brain through immunotherapy, antisense oligonucleotides, and siRNA. MAPT codes for Tau, therefore understanding how the MAPT gene is regulated and the effect of genetic variation at its regulatory elements is likely to have high relevance for tauopathies. We screened a ~3 Mb region including the MAPT locus using 2 different massively parallel reporter assay (MPRA) strategies in KOLF2.1J h-NGN2 neurons and HEK293FT cells, identifying previously unannotated cis-regulatory elements (CREs). Using CRISPR interference (CRISPRi) in mixed neuron cultures, we identified a new CRE for MAPT, as well as 2 CREs for another nearby gene of interest, KANSL1. Known genetic variation from the Alzheimer's Disease sequencing project was tested in a separate MPRA at the top CREs near the MAPT gene, identifying variants with altered regulatory effects including those at previously identified CREs for MAPT. Using a saturation mutagenesis screen of a 2,000 bp region encompassing the MAPT promoter, we assessed regulatory effects of each possible single nucleotide variant in this region. We identified several neuron-specific regulatory variant effects at this region, including a high confidence binding site for the transcription factors EGR2, ZBTB14 and TCLF5 at a region of high MPRA activity and genetic conservation.
2026-03-20 | GSE325585 | GEO
Project description:Tau neurofibrillary tangles are a hallmark of several neurodegenerative diseases called tauopathies, including frontotemporal dementia and Alzheimer's Disease. Ongoing clinical trials for tauopathies seek to reduce Tau in the brain through immunotherapy, antisense oligonucleotides, and siRNA. MAPT codes for Tau, therefore understanding how the MAPT gene is regulated and the effect of genetic variation at its regulatory elements is likely to have high relevance for tauopathies. We screened a ~3 Mb region including the MAPT locus using 2 different massively parallel reporter assay (MPRA) strategies in KOLF2.1J h-NGN2 neurons and HEK293FT cells, identifying previously unannotated cis-regulatory elements (CREs). Using CRISPR interference (CRISPRi) in mixed neuron cultures, we identified a new CRE for MAPT, as well as 2 CREs for another nearby gene of interest, KANSL1. Known genetic variation from the Alzheimer's Disease sequencing project was tested in a separate MPRA at the top CREs near the MAPT gene, identifying variants with altered regulatory effects including those at previously identified CREs for MAPT. Using a saturation mutagenesis screen of a 2,000 bp region encompassing the MAPT promoter, we assessed regulatory effects of each possible single nucleotide variant in this region. We identified several neuron-specific regulatory variant effects at this region, including a high confidence binding site for the transcription factors EGR2, ZBTB14 and TCLF5 at a region of high MPRA activity and genetic conservation.
2026-03-10 | GSE324430 | GEO
Project description:Tau neurofibrillary tangles are a hallmark of several neurodegenerative diseases called tauopathies, including frontotemporal dementia and Alzheimer's Disease. Ongoing clinical trials for tauopathies seek to reduce Tau in the brain through immunotherapy, antisense oligonucleotides, and siRNA. MAPT codes for Tau, therefore understanding how the MAPT gene is regulated and the effect of genetic variation at its regulatory elements is likely to have high relevance for tauopathies. We screened a ~3 Mb region including the MAPT locus using 2 different massively parallel reporter assay (MPRA) strategies in KOLF2.1J h-NGN2 neurons and HEK293FT cells, identifying previously unannotated cis-regulatory elements (CREs). Using CRISPR interference (CRISPRi) in mixed neuron cultures, we identified a new CRE for MAPT, as well as 2 CREs for another nearby gene of interest, KANSL1. Known genetic variation from the Alzheimer's Disease sequencing project was tested in a separate MPRA at the top CREs near the MAPT gene, identifying variants with altered regulatory effects including those at previously identified CREs for MAPT. Using a saturation mutagenesis screen of a 2,000 bp region encompassing the MAPT promoter, we assessed regulatory effects of each possible single nucleotide variant in this region. We identified several neuron-specific regulatory variant effects at this region, including a high confidence binding site for the transcription factors EGR2, ZBTB14 and TCLF5 at a region of high MPRA activity and genetic conservation.
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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: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: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