Engineered Wnt7a ligands rescue blood–brain barrier and cognitive deficits in a COVID-19 mouse model

Brain, Год журнала: 2024, Номер 147(5), С. 1636 - 1643

Опубликована: Фев. 2, 2024

Abstract Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction following mild respiratory infection. To this end, we performed unbiased transcriptional analysis brain endothelial cell signalling pathways dysregulated by mouse adapted MA10 in aged immunocompetent C57Bl/6 mice vivo. This revealed significant suppression of Wnt/β-catenin signalling, a critical regulator blood–brain barrier (BBB) integrity. therefore hypothesized that enhancing activity would offer protection against BBB permeability, neuroinflammation, neurological signs acute Indeed, found delivery cerebrovascular-targeted, engineered Wnt7a ligands protected integrity, reduced T-cell infiltration brain, microglial activation Importantly, strategy also mitigated induced deficits novel object recognition assay for learning memory pole descent task bradykinesia. These observations suggest enhancement or its downstream effectors could be potential interventional strategies restoring health viral infections.

Язык: Английский

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The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 5601 - 5601

Опубликована: Май 21, 2024

This review addresses the role of tight junction proteins at blood-brain barrier (BBB). Their expression is described, and their in physiological pathological processes BBB discussed. Based on this, new approaches are depicted for paracellular drug delivery diagnostics treatment cerebral diseases. Recent data provide convincing evidence that, addition to its impairment course diseases, could be involved aetiology CNS disorders. Further progress will expected based insights protein structure involvement signalling pathways.

Язык: Английский

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Direct and indirect impact of SARS-CoV-2 on the brain

Human Genetics, Год журнала: 2023, Номер 142(8), С. 1317 - 1326

Опубликована: Апрель 1, 2023

Язык: Английский

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Caveolin-1 mediates blood-brain barrier permeability, neuroinflammation, and cognitive impairment in SARS-CoV-2 infection

Journal of Neuroimmunology, Год журнала: 2024, Номер 388, С. 578309 - 578309

Опубликована: Фев. 4, 2024

Blood-brain barrier (BBB) permeability can cause neuroinflammation and cognitive impairment. Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on the consequent neurological outcomes in respiratory viral infections is unknown. We used Cav-1-deficient mice with genetically encoded fluorescent endothelial tight junctions to determine how Cav-1 influences neuroinflammation, impairment following infection mouse adapted (MA10) SARS-CoV-2 as a model for COVID-19. found that increased brain transcellular albumin, decreased paracellular Claudin-5 junctions, caused T lymphocyte infiltration hippocampus, region important learning memory. Concordantly, we observed memory deficits infected mice. Importantly, genetic deficiency attenuated junction losses, infiltration, gliosis induced by infection. Moreover, KO were protected from These results establish contribution of behavioral dysfunction neuroinflammation.

Язык: Английский

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Animal models to study the neurological manifestations of the post-COVID-19 condition

Lab Animal, Год журнала: 2023, Номер 52(9), С. 202 - 210

Опубликована: Авг. 24, 2023

Abstract More than 40% of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have experienced persistent or relapsing multi-systemic symptoms months after the onset disease 2019 (COVID-19). This post-COVID-19 condition (PCC) has debilitating effects on daily life patients and encompasses a broad spectrum neurological neuropsychiatric including olfactory gustative impairment, difficulty with concentration short-term memory, sleep disorders depression. Animal models been instrumental to understand COVID-19 validate prophylactic therapeutic interventions. Similarly, studies post-viral clearance in hamsters, mice nonhuman primates inoculated SARS-CoV-2 useful unveil some aspects PCC. Transcriptomic alterations central nervous system, activation immune cells impaired hippocampal neurogenesis seem critical role manifestations observed animal SARS-CoV-2. Interestingly, proinflammatory transcriptomic profile system SARS-CoV-2-inoculated partially overlaps pathological changes that affect microglia humans during Alzheimer’s aging, suggesting shared mechanisms between these conditions. None currently available fully replicates PCC humans; therefore, multiple models, together fine-tuning experimental conditions, will probably be needed symptoms. Moreover, given intrinsic characteristics new variants concern immunological status might influence manifestations, more are explore factors their combinations PCC, adding further complexity design models.

Язык: Английский

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Animal models of Long Covid: A hit-and-run disease

Science Translational Medicine, Год журнала: 2024, Номер 16(773)

Опубликована: Ноя. 13, 2024

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) pandemic has caused more than 7 million deaths globally. Despite the presence of infection- and vaccine-induced immunity, SARS-CoV-2 infections remain a major global health concern because emergence variants that can cause disease 2019 (COVID-19) or enhance Long Covid phenotypes. About 5 to 10% SARS-CoV-2-infected individuals develop Covid, which, similar COVID 19, often affects lung. However, also affect other peripheral organs, especially brain. causal relationships between phenotypes, long-term symptoms, involvement multiple organ systems elusive, animal model mimicking both post-acute phases are imperative. Here, we review current state models, including possible future applications.

Язык: Английский

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COVID‐19 and the impact on Alzheimer's disease pathology

Journal of Neurochemistry, Год журнала: 2023, Номер unknown

Опубликована: Окт. 18, 2023

Abstract Coronavirus disease 2019 (COVID‐19) has rapidly escalated into a global pandemic that primarily affects older and immunocompromised individuals due to underlying clinical conditions suppressed immune responses. Furthermore, COVID‐19 patients exhibit spectrum of neurological symptoms, indicating can affect the brain in variety manners. Many studies, past recent, suggest connection between viral infections an increased risk neurodegeneration, raising concerns about effects possibility it may contribute Alzheimer's (AD) onset or worsen already existing AD pathology through inflammatory processes given both share pathological features factors. This leads us question whether is factor for how these two might influence each other. Considering extensive reach devastating impact ongoing pandemic, their combined could have significant public health consequences worldwide. image

Язык: Английский

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Mouse Adapted SARS-CoV-2 Model Induces “Long-COVID” Neuropathology in BALB/c Mice

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 20, 2023

Abstract The novel coronavirus SARS-CoV-2 has caused significant global morbidity and mortality continues to burden patients with persisting neurological dysfunction. COVID-19 survivors develop debilitating symptoms include neuro-psychological dysfunction, termed “Long COVID”, which can cause reduction of quality life. Despite vigorous model development, the possible these underlying pathophysiology this devastating disease remains elusive. Mouse adapted (MA10) is a mouse-based simulates clinical respiratory distress associated infection in mice. In study, we evaluated long-term effects MA10 on brain pathology neuroinflammation. 10-week 1-year old female BALB/cAnNHsd mice were infected intranasally 10 4 plaque-forming units (PFU) 3 PFU MA10, respectively, was examined 60 days post-infection (dpi). Immunohistochemical analysis showed decrease neuronal nuclear protein NeuN an increase Iba-1 positive amoeboid microglia hippocampus after infection, indicating changes area critical for memory consolidation processing. Importantly, seen 40-50% mice, correlates prevalence LC clinically. Our data shows first time that induces neuropathological outcomes several weeks at similar rates observed COVID”. These observations strengthen as viable study humans. Establishing viability key step towards rapid development therapeutic strategies ameliorate neuroinflammation restore function those suffering from persistent cognitive dysfunction “Long-COVID”.

Язык: Английский

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Animal Models of Non-Respiratory, Post-Acute Sequelae of COVID-19

Viruses, Год журнала: 2025, Номер 17(1), С. 98 - 98

Опубликована: Янв. 14, 2025

Post-acute sequelae of COVID-19 (PASC) are a diverse set symptoms and syndromes driven by dysfunction multiple organ systems that can persist for years negatively impact the quality life millions individuals. We currently lack specific therapeutics patients with PASC, due in part to an incomplete understanding its pathogenesis, especially non-pulmonary sequelae. Here, we discuss three animal models have been utilized investigate PASC: non-human primates (NHPs), hamsters, mice. focus on neurological, gastrointestinal, cardiovascular PASC highlight advances mechanistic insight made using these models, as well discussing warrant continued intensive research.

Язык: Английский

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Animal models of post-acute COVID-19 syndrome: a call for longitudinal animal studies

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 26, 2025

Animal models are indispensable for unraveling the mechanisms underlying post-acute sequelae of COVID-19 (PASC). This review evaluates recent research on PASC-related perturbations in animal models, drawing comparisons with clinical findings. Despite limited number studies post-COVID conditions, particularly those extending beyond three months, these provide valuable insights. Three hallmark features PASC-lung fibrosis, hyperglycemia, and neurological sequelae-have been successfully replicated paving way mechanistic discoveries future medical interventions. Although most have reported conditions within 14-60 days post-infection, they still offer critical reference long-term research. also explores potential persisting immune misfiring, a key factor chronicity PASC symptoms. Moreover, challenges modeling discussed, including genetic diversity inbred strains difficulties accurately identifying PASC-affected individuals. To address issues, we propose methodological improvements, such as comparing individual parameters control averages incorporating genetically diverse populations like collaborative cross models. These strategies will enhance identification characterization endotypes studies. By integrating findings from manifestations PASC, can more insights into its support development effective therapeutic strategies. Finally, emphasize urgent need longitudinal to fully uncover driving guide interventions mitigate public health impact.

Язык: Английский

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