TREM2 supports neuronal protection and microglial reactivity independently of affecting misfolded protein deposition in chronic neurodegenerative prion disease
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ABSTRACT:
PROVIDER: PRJNA1181846 | ENA |
REPOSITORIES: ENA
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Project description:TREM2 (triggering receptor expressed on myeloid cells-2) variants have been identified as risk factors for neurodegenerative disease including Alzheimer’s disease. TREM2 is a cell surface receptor on microglia that regulates homeostatic and immunomodulatory functions including phagocytosis of apoptotic debris and the resolution of damage-associated inflammation. It remains unclear how TREM2 may mediate an influence on neurodegenerative disease, particularly in relation to key neuropathological hallmarks such as neuronal loss and proteinopathy. We used the ME7 prion disease model to assess the role of TREM2 in the progression and pathology of neurodegenerative disease. Prion diseases are characterised by the accumulation of misfolded prion protein and provide a highly tractable platform to determine if TREM2 has disease-modifying effects. Trem2-/- and wild type mice were inoculated intracerebrally with mouse-passaged ME7 scrapie prions and effects on CNS disease pathogenesis determined. Although the accumulation of prion disease-specific PrP was similar in the brains of mice from each group, the severity of the neuropathology was increased in Trem2-/- mice. Morphometric analysis of the microglia also indicated blunted disease-induced reactivity in the brains of infected Trem2-/- mice compared to wild type (WT) controls. The expression of genes involved in myelination were reduced in prion-infected Trem2-/- mice compared to infected WT mice. We conclude that during infection of the brain with prions, TREM2 supports microglial reactive changes that are associated with resilience to neuronal loss independently of affecting misfolded PrP deposition. These data imply that TREM2 status may be an important influence on the downstream response to CNS proteinopathy that alters the susceptibility of neurons and brain tissue to proteinopathy-induced degenerative changes.
2025-05-30 | GSE281022 | GEO
Project description:Currently there are no treatments that can slow or halt the progression of dementia’s including Alzheimer’s disease. Here we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which shows many of the pathological hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulated as well as a normalisation in the expression of markers associated neurodegeneration and Alzheimer’s disease. Furthermore, synaptic proteins and post-synaptic signalling components disrupted in disease are maintained by VU846. We conclude that allosteric regulation of M1-receptors have the potential to reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.
2023-03-14 | PXD025561 | Pride
Project description:Understanding why certain neurons are more sensitive to dysfunction and death caused by misfolded proteins could provide therapeutically relevant insights into neurodegenerative disorders. Here, we harnessed single-cell transcriptomics to examine live neurons isolated from prion-infected female mice, aiming to identify and characterize prion-vulnerable neuronal subsets. Our analysis revealed distinct transcriptional responses across neuronal subsets, with a consistent pathway-level depletion of synaptic gene expression in damage-vulnerable neurons. By scoring neuronal damage based on the magnitude of depleted synaptic gene expression, we identified a diverse spectrum of prion-vulnerable glutamatergic, GABAergic, and medium spiny neurons. Comparison between prion-vulnerable and resistant neurons highlighted baseline gene expression differences that could influence neuronal vulnerability. For instance, the neuroprotective cold-shock protein Rbm3 exhibited higher baseline gene expression in prion-resistant neurons and was robustly upregulated across diverse neuronal classes upon prion infection. We also identified vulnerability-correlated transcripts that overlapped between prion and Alzheimer’s disease. Our findings not only demonstrate the potential of single-cell transcriptomics to identify damage-vulnerable neurons, but also provide molecular insights into neuronal vulnerability and highlight commonalties across neurodegenerative disorders.
2024-10-25 | GSE249382 | GEO
Project description:Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.
2023-01-31 | GSE214373 | GEO
Project description:Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.
2023-01-31 | GSE214375 | GEO
Project description:Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.
2023-01-31 | GSE214374 | GEO
Project description:Purpose: evaluation of the neuroprotective effects of VU846 compound, a positive allosteric modulator highly specific for the M1 muscarinic receptor, using the Next-generation sequencing (NGS) technology in a context of neurodegeneration induced by prion disease. Methods: Tg37 hemizygous mice at 3 to 4 weeks were inoculated with either the Rocky Mountain Laboratory (RML) scrapie prion brain homogenate, causative of the neurodegeneration, or normal brain homogenate for control purposes. Mice were also daily injected with either the M1 specific positive allosteric modulator VU836 or vehicle. The drug treatment started at 7week post brain homogenate inoculations (wpi) and 11wpi. The hippocampi from 3 mice of each group (control + vehicle, control + VU846, prion + vehicle and prion + VU846) were subject to tot RNA extraction. Raw reads were then converted into Fastq format, mapped to the “mouse-mm10” genome using HISAT2 (Galaxy Version 2.1.0) and processed with the StringTie (Galaxy Version 1.3.3.2) for assembling and quantification. Differential gene expression comparisons were performed with DESeq2 statistical tool (Galaxy Version 2.11.40.2) and data further analysed with two online software suites, Gene Ontology Panther (http://www.pantherdb.org/) and Pathway Studio (www.pathwaystudio.com). Results: we use the bioinformatic tool Pathway Studio (www.pathwaystudio.com) to quantitatively assesses the changes in the transcriptome with gene functions reported in the literature to assign an actication score. Strikingly, up and down regulation of genes changed by prion disease promote neuroinflammation and Alzheimer’s disease (AD) (positive activation scores), whereas the M1R specific positive allosteric modulator VU846 treatment modified the expression of genes to inhibit the neuroinflammatory and neurodegenerative processes directly associated with AD (negative activation score). Among these are genes associated with the complement system, microglia and astrocyte activation. Furthermore, consistent with the notion that neuroinflammatory pathways were activated in prion disease and diminished by VU846, the GO Pathway analysis revealed enrichment of genes in pathways such as the complement cascade and chemokine/cytokine signalling. Conversely, a group of genes that were down-regulated in prion disease were transcribed at significantly higher levels in the prion-effect of animals treated with VU846. These genes were strongly associated with synaptic plasticity, learning and memory, cognition and synaptic transmission by the GO Pathway analysis. Conclusions: These data point to the possibility that specific features of neuroinflammation and disease-adaptation may be directly regulated by M1-receptor activity strongly reinforcing the concept that pharmaceutically targeting M1 muscarinic receptor is neuroprotective and it might lead to the development of new treatments of Alzheimer’s like neurodegenerative diseases.
2023-05-04 | GSE202275 | GEO
Project description:Prion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we observed were specific to PrP targeted to the plasma membrane since these prion-induced gene expression changes were not evident in similarly-treated Drosophila transgenic for cytosolic pan neuronal PrP expression, or in non-transgenic control flies. Collectively, our data indicate that aberrant cell cycle activity, repression of protein synthesis and altered mitochondrial function are key events involved in prion-induced neurotoxicity, and correlate with those identified in mammalian hosts undergoing prion disease. These studies highlight the use of PrP transgenic Drosophila as a genetically well-defined tractable host to study mammalian prion biology.
2020-01-31 | GSE144028 | GEO
Project description:Sheep scrapie is a transmissible spongiform encephalopathy (TSE), which are invariably fatalM- neurodegenerative diseases of the central nervous system (CNS). Accumulation of the misfolded prion protein, PrPSc in the CNS results in progressive neurodegenerative disease. Susceptible VRQ homozygous New Zealand Cheviot sheep were infected with standard scrapie sheep prion (SSBP/1) scrapie by inoculation in the drainage area of the prescapular lymph nodes. PrPSc was consistently detected by immunohistology in the CNS at XX days post infection (dpi). This study compares the genes and physiological pathways that are affected by the progression of TSE disease in the CNS, focusing on time points immediately before (XX dpi) and after (XX dpi) the detection of disease-associated PrPSc.
2014-06-01 | E-MTAB-2369 | biostudies-arrayexpress
Project description:Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal, benign forms of prion protein (PrPC) to disease-causing PrPSc isoforms. A systems approach to disease postulates that disease arises from the pathological perturbation (genetic and/or environmental) of one or more biological networks in the relevant organ. In this regard, we tracked global (all mRNA transcripts) gene expression in the brains of eight distinct mouse strain-prion strain combinations at 8 - 10 time points throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Data are also available from http://prion.systemsbiology.net
2009-03-25 | E-MTAB-76 | biostudies-arrayexpress