Reactive astrocytes associated with prion disease impair the blood brain barrier

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 185, P. 106264 - 106264

Published: Aug. 18, 2023

Impairment of the blood-brain barrier (BBB) is considered to be a common feature among neurodegenerative diseases, including Alzheimer's, Parkinson's and prion diseases. In disease, increased BBB permeability was reported 40 years ago, yet mechanisms behind loss integrity have never been explored. Recently, we showed that reactive astrocytes associated with diseases are neurotoxic. The current work examines potential link between astrocyte reactivity breakdown. prion-infected mice, aberrant localization aquaporin 4 (AQP4), sign retraction astrocytic endfeet from blood vessels, were noticeable prior disease onset. Gaps in cell-to-cell junctions along together downregulation Occludin, Claudin-5 VE-cadherin, which constitute tight adherens junctions, suggested linked degeneration vascular endothelial cells. contrast cells isolated non-infected adult originating mice displayed disease-associated changes, lower levels VE-cadherin expression, impaired reduced trans-endothelial electrical resistance (TEER). Endothelial when co-cultured animals or treated media conditioned by astrocytes, developed phenotype observed mice. Reactive found produce high secreted IL-6, treatment monolayers recombinant IL-6 alone their TEER. Remarkably, extracellular vesicles produced normal partially reversed animals. To our knowledge, first illustrate early breakdown document detrimental integrity. Moreover, findings suggest harmful effects proinflammatory factors astrocytes.

Language: Английский

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Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(4), P. e1012087 - e1012087

Published: April 1, 2024

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic infectious versions, while mutant cause inherited variants like fatal familial insomnia (FFI) Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold rodent models of diseases, no effective treatments FFI fCJD have been found. In this study, we evaluated efficacy various anti-prion on newly-developed knock-in mouse fCJD. These express bank vole protein (PrP) with pathogenic D178N E200K mutations. We applied drug regimens known be highly against wild-type vivo as well a brain-penetrant compound that inhibits PrP Sc propagation vitro . None tested (Anle138b, IND24, Anle138b + cellulose ether, PSCMA) significantly extended disease-free survival or prevented accumulation either model, despite their ability induce strain adaptation prions. Our results show originally developed treat do not necessarily work recombinant sPMCA is reliable platform identifying compounds target This underscores need develop therapies validate screening assays specifically prions, strategies strain-dependent.

Language: Английский

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Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(2)

Published: Jan. 18, 2023

There is an urgent need to develop drugs for prion disease, a currently untreatable neurodegenerative disease. In this effort, there debate over which animal models can best support drug development program.

Language: Английский

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Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies

Biology, Journal Year: 2024, Volume and Issue: 13(2), P. 67 - 67

Published: Jan. 23, 2024

Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across regions, mixture cell types therein obscures experimental results. In recent years, methods that analyze transcriptomes individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and provided invaluable specific types. Concurrently, transgene-based techniques dissect type-specific translatomes (CSTs) in model systems, like RiboTag bacTRAP, unique advantages but received less attention. This review juxtaposes merits drawbacks both methodologies, focusing use CSTs understanding conditions amyotrophic lateral sclerosis (ALS), Huntington’s (HD), Alzheimer’s (AD), prion fatal familial insomnia (FFI), genetic Creutzfeldt–Jakob (gCJD), acquired disease. We conclude by discussing emerging trends observed multiple methods.

Language: Английский

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Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons

Life Science Alliance, Journal Year: 2022, Volume and Issue: 5(11), P. e202201530 - e202201530

Published: Oct. 3, 2022

Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, including fatal familial insomnia (FFI) and Creutzfeldt–Jakob disease (CJD), different mutations the Prnp gene manifest as clinically neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased 21 mo old knock-in mice modeling FFI CJD sleep mildy affected mice. To define cell types, analyzed type–specific translatomes from six neuron types of 9 Somatostatin (SST) neurons responded strongest both unexpectedly high overlap genes pathways. Functional analyses revealed up-regulation pathways ribosome mitochondria biogenesis, down-regulation synaptic function small GTPase-mediated signaling FFI, implicating mTOR root these changes. contrast, responses glutamatergic cerebellar were disease-specific. The similarity SST suggests a therapy may be beneficial for multiple

Language: Английский

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Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease

Acta Neuropathologica Communications, Journal Year: 2022, Volume and Issue: 10(1)

Published: Nov. 9, 2022

Abstract Prion diseases are neurodegenerative disorders with long asymptomatic incubation periods, followed by a rapid progression of cognitive and functional decline culminating in death. The complexity intercellular interactions the brain is challenging to unravel basis disease pathobiology remains poorly understood. In this study, we employed single cell RNA sequencing (scRNAseq) produce an atlas 147,536 transcriptomes from cortex hippocampus mice infected prions showing clinical signs. We identified transcriptionally distinct populations sub-populations all major cell-types. Disease-related transcription was highly specific not only overarching cell-types, but also glia neurons. Most striking apparent decrease relative frequency astrocytes expressing genes that required for homeostasis such as lipid synthesis, glutamate clearance, synaptic modulation regulation blood flow. Additionally, described spectrum microglial activation states suggest delineation phagocytic neuroinflammatory functions different subsets. Differential responses immature mature neuron were observed, alongside abnormal hippocampal neurogenesis. Our scRNAseq library provides new layer knowledge on gene expression prion disease, more detailed understanding cellular interplay leads neurodegeneration.

Language: Английский

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Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntington’s disease mice

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: Jan. 20, 2023

Abstract Although Huntington’s disease (HD) is classically defined by the selective vulnerability of striatal projection neurons, there increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little known about cell type-specific responses neurons in HD. To dissect early mechanisms cerebellum and cerebrum, we analyzed translatomes neuronal types from both regions a new HD mouse model. For this, HdhQ200 knock-in mice were backcrossed with calm 129S4 strain, to constrain experimental noise caused variable hyperactivity C57BL/6 background. Behavioral neuropathological characterization showed these S4-HdhQ200 had very mild behavioral abnormalities starting around 12 months age remained up 18 months. By 9 months, observed abundant Huntingtin-positive intranuclear inclusions (NIIs) striatum cerebellum. The translatome analysis GABAergic cells cerebrum further confirmed changes typical HD-induced pathology. Surprisingly, strongest response 626 differentially expressed genes glutamatergic cerebellum, population consisting primarily granule cells, commonly considered resistant. Our findings suggest vesicular fusion exocytosis, as well differentiation-related pathways are affected neurons. Furthermore, increased expression cyclin D1 ( Ccnd1 ) granular layer upregulated polycomb group complex protein cycle regulators Cbx2, Cbx4 Cbx8 point putative role aberrant regulation disease.

Language: Английский

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Translatome and transcriptome profiling of neonatal mice hippocampus exposed to sevoflurane anesthesia

Heliyon, Journal Year: 2024, Volume and Issue: 10(9), P. e28876 - e28876

Published: April 12, 2024

Exposure to anesthesia in early life may cause severe damage the brain and lead cognitive impairment. The underlying mechanisms, which have only been investigated a limited scale, remains largely elusive. We performed translatome transcriptome sequencing together for first time hippocampus of neonatal mice that were exposed sevoflurane. treated group with 2.5 % sevoflurane 2 h on day 6, 7, 8, 9 another 7. behavioral study after 30 both groups control evaluate On 36, we collected from two groups, compared gene expression levels between control, validated results RT-qPCR. identified 1750 differentially expressed genes (DEGs) comparison 1109 DEGs comparison. As expected, translatome-based significantly overlapped transcriptome-based DEGs, functional enrichment analysis generated similar enriched cognition-related GO terms KEGG pathways. However, many like Hspa5, their alterations differed remarkably those transcriptome, Western blot concordant former, suggesting translational regulation plays significant role cellular response Our revealed global exposure highlighted importance understanding mechanisms responsible anesthesia-induced

Language: Английский

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Prion diseases disrupt glutamate/glutamine metabolism in skeletal muscle

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(9), P. e1012552 - e1012552

Published: Sept. 11, 2024

In prion diseases (PrDs), aggregates of misfolded protein (PrP Sc ) accumulate not only in the brain but also extraneural organs. This raises question whether prion-specific pathologies arise extraneurally. Here we sequenced mRNA transcripts skeletal muscle, spleen and blood prion-inoculated mice at eight timepoints during disease progression. We detected gene-expression changes all three organs, with muscle showing most consistent alterations. The glutamate-ammonia ligase ( GLUL gene exhibited uniform upregulation muscles infected distinct scrapie strains (RML, ME7, 22L) victims human sporadic Creutzfeldt-Jakob disease. dysregulation was accompanied by glutamate/glutamine metabolism, leading to reduced glutamate levels muscle. None these were observed humans amyotrophic lateral sclerosis, Alzheimer’s disease, or dementia Lewy bodies, suggesting that they are specific diseases. These findings reveal an unexpected metabolic dimension infections point a potential role for metabolism prion-affected

Language: Английский

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Reactive astrocytes associated with prion disease impair the blood brain barrier

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 25, 2023

Impairment of the blood-brain barrier (BBB) is considered to be a common feature among neurodegenerative diseases, including Alzheimer's, Parkinson's and prion diseases. In disease, increased BBB permeability was reported 40 years ago, yet mechanisms behind loss integrity have never been explored. Recently, we showed that reactive astrocytes associated with diseases are neurotoxic. The current work examines potential link between astrocyte reactivity breakdown.In prion-infected mice, aberrant localization aquaporin 4 (AQP4), sign retraction astrocytic endfeet from blood vessels, were noticeable prior disease onset. Gaps in cell-to-cell junctions along together downregulation Occludin, Claudin-5 VE-cadherin, which constitute tight adherens junctions, suggested linked degeneration vascular endothelial cells. contrast cells isolated non-infected adult originating mice displayed disease-associated changes, lower levels VE-cadherin expression, impaired reduced trans-endothelial electrical resistance (TEER). Endothelial when co-cultured animals or treated media conditioned by astrocytes, developed phenotype observed mice. Reactive found produce high secreted IL-6, treatment monolayers recombinant IL-6 alone their TEER. Remarkably, extracellular vesicles produced normal partially reversed animals.To our knowledge, first illustrate early breakdown document detrimental integrity. Moreover, findings suggest harmful effects proinflammatory factors astrocytes.

Language: Английский

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