Reactive astrocytes associated with prion disease impair the blood brain barrier

Neurobiology of Disease, Год журнала: 2023, Номер 185, С. 106264 - 106264

Опубликована: Авг. 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.

Язык: Английский

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Identification of M4 muscarinic acetylcholine receptor expressing astrocytes that regulate locomotion and survival in murine prion disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

Abstract Whilst there has been much focus on the function of neuronally expressed members muscarinic acetylcholine receptor family (mAChR) less attention paid to expression profile and role five this (M 1 -M 5 mAChRs) in non-neuronal cells brain. Using genetically engineered mice we identify a previously unappreciated sub-population astrocytes expressing M 4 mAChR subtype. These are located various brain regions that include brainstem, hypothalamus and, most abundantly, cerebellum. Signalling proteomic analysis positive from cerebellum established functional subtype its regulation protein expression. Genetic ablation revealed specific locomotion behaviour. Importantly, context murine prion disease, model terminal neurodegeneration associated with profound neuroinflammation, observed significant expansion report experiments astrocyte detrimental effect late-stage disease. Together provide evidence play normal neurophysiology progression inflammatory neurodegenerative

Язык: Английский

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Mechanisms of prion-induced toxicity

Cell and Tissue Research, Год журнала: 2022, Номер 392(1), С. 81 - 96

Опубликована: Сен. 7, 2022

Язык: Английский

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Region-Specific Homeostatic Identity of Astrocytes Is Essential for Defining Their Response to Pathological Insults

Cells, Год журнала: 2023, Номер 12(17), С. 2172 - 2172

Опубликована: Авг. 30, 2023

The transformation of astrocytes into reactive states constitutes a biological response the central nervous system under variety pathological insults. Astrocytes display diverse homeostatic identities that are developmentally predetermined and regionally specified. Upon associated with neurodegenerative diseases other neurological disorders, acquire phenotypes. However, it is not clear whether their phenotypes dictated by region-specific identity or nature an insult. To address this question, gene expression profiling was performed for four brain regions (cortex, hippocampus, thalamus, hypothalamus) in mice using custom NanoString panel consisting selected sets genes astrocyte functions reactivity five conditions: prion disease, traumatic injury, ischemia, 5XFAD Alzheimer’s disease model normal aging. states, predominantly were found to respond insults manner. Regardless insult insult-specificity response, strong correlations between undirected GSA (gene set analysis) scores reporting on observed within each individual region. insult-specific signatures did separate well from instead partially overlapped, forming continuums. current study demonstrates important defining Within populations, show continuums signatures, overlapping

Язык: Английский

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Distinct patterns of prion strain deposition and toxicity in a novel whole brain organotypic slice culture system

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 8, 2025

Prion diseases are fatal transmissible neurodegenerative that affect many mammals, including humans, caused by the templated misfolding of prion protein. Different conformations misfolded prions can occur, leading to distinct disease phenotypes or strains and accumulation in brain regions. How structure influences this tropism is not clear, but nature has allowed for development ex vivo slice models disease. To date, work been done cerebellar cultures, known differentially other We have adapted approach a coronally sliced whole organotypic culture demonstrate profiles cytotoxicity neuronal loss upon exposure four mouse-adapted scrapie strains. were able induce infection both diffusely through submersion cultures infectious media locally contact with prion-coated stainless-steel wires. Moreover, we observed consistent strain-specific regional differences deposition 8 weeks infection, recapitulating what seen vivo. predict coronal be powerful tool elucidating mechanisms spread pathology.

Язык: Английский

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Phagocytic Activities of Reactive Microglia and Astrocytes Associated with Prion Diseases Are Dysregulated in Opposite Directions

Cells, Год журнала: 2021, Номер 10(7), С. 1728 - 1728

Опубликована: Июль 8, 2021

Phagocytosis is one of the most important physiological functions glia directed at maintaining a healthy, homeostatic environment in brain. Under environment, phagocytic activities astrocytes and microglia are tightly coordinated time space. In neurodegenerative diseases, both contribute to neuroinflammation disease pathogenesis, however, whether their up- or downregulated reactive states not known. To address this question, current study isolated from C57BL/6J mice infected with prions tested live-cell imaging assays that used synaptosomes myelin debris as substrates. The uptake by was found be significantly upregulated, whereas strongly downregulated. downregulation phagocytosis two cell types were observed irrespective disease-associated synaptosomes, normal assays, indicating dysregulations dictated states, Analysis gene expression confirmed dysregulation types. Immunostaining animal brains revealed terminal stage disease, neuronal bodies subject engulfment microglia. This suggests imbalance astrocytes, which dysregulated opposite directions, likely lead excessive microglia-mediated death on hand, inability clear other contributing neurotoxic effects whole.

Язык: Английский

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Distinct translatome changes in specific neural populations precede electroencephalographic changes in prion-infected mice

PLoS Pathogens, Год журнала: 2022, Номер 18(8), С. e1010747 - e1010747

Опубликована: Авг. 12, 2022

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific cell types and brain regions. Using the RiboTag method mice, translational responses five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset onset timepoints chosen based on longitudinal electroencephalography (EEG) that revealed gradual increase theta power between 10- 18-weeks after injection, resembling clinical human PrD. At onset, marked by significantly increased histopathological lesions, mice had pronounced translatome changes all despite appearing normal. Remarkably, at pre-onset stage, prior EEG neuropathological changes, we found 1) translatomes astrocytes indicated reduced synthesis ribosomal mitochondrial components, 2) glutamatergic neurons showed expression cytoskeletal genes, 3) GABAergic circadian rhythm genes. These data demonstrate early neurodegeneration emerge conventional markers are type-specific. Therapeutic strategies may need target multiple pathways populations cells, disease.

Язык: Английский

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Strain-Specific Targeting and Destruction of Cells by Prions

Biology, Год журнала: 2024, Номер 13(1), С. 57 - 57

Опубликована: Янв. 20, 2024

Prion diseases are caused by the disease-specific self-templating infectious conformation of host-encoded prion protein, PrPSc. strains operationally defined as a heritable phenotype disease under controlled conditions. One hallmark phenotypes strain diversity is tropism within and between tissues. A defining feature regional distribution PrPSc in CNS. Additionally, both natural experimental disease, stark differences prions secondary lymphoreticular system tissues occur. The mechanism underlying unknown; however, several possible hypotheses have been proposed. Clinical target areas strain-specific populations neurons CNS that susceptible to neurodegeneration following replication past toxic threshold. Alternatively, switch from replicative form may drive tropism. normal PrPC, required for formation. More recent evidence suggests it can mediate prion-like neurodegeneration. In vitro systems formation indicated cellular cofactors contribute Since these be specific, this has led hypothesis influence Overall, there support mechanisms tropism; unified theory yet emerge.

Язык: Английский

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The Role of Glial Cells in Neurobiology and Prion Neuropathology

Cells, Год журнала: 2024, Номер 13(10), С. 832 - 832

Опубликована: Май 14, 2024

Prion diseases are rare and neurodegenerative that characterized by the misfolding infectious spread of prion protein in brain, causing progressive irreversible neuronal loss associated clinical behavioral manifestations humans animals, ultimately leading to death. The brain has a complex network neurons glial cells whose crosstalk is critical for function homeostasis. Although it established infection necessary disease occur, debate remains field as role played cells, namely astrocytes microglia, whether these beneficial host or further accelerate disease. Here, we review current literature assessing morphologies between two cell types, prion-infected brain.

Язык: Английский

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Role of sialylation of N-linked glycans in prion pathogenesis

Cell and Tissue Research, Год журнала: 2022, Номер 392(1), С. 201 - 214

Опубликована: Янв. 28, 2022

Язык: Английский

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