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Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction (preprint)
biorxiv; 2022.
Preprint
in English
| bioRxiv | ID: ppzbmed-10.1101.2022.06.02.494552
ABSTRACT
Persistent cognitive impairment and neuropsychiatric disorders are prevalent sequelae of SARS-CoV-2-induced COVID-19 in middle-aged adults. To model age-related neurological vulnerability to COVID-19, we induced respiratory SARS-CoV-2 MA10 infections by nasal inoculation in young (2 months) and middle-aged (12 months) mice. We hypothesized that aging and SARS-CoV-2 synergistically damage the blood-brain barrier (BBB). Indeed, the combined action of aging and SARS-CoV-2 infection caused more fibrinogen leakage, T cell infiltration, and neuroinflammation in middle-aged SARS-CoV-2-infected mice than in similarly inoculated young adults. Mechanistically, SARS-CoV-2 exacerbated age-related increases in Caveolin-1 BBB transcellular permeability and loss of Wnt/β-catenin ligands, with no apparent changes in tight junction proteins. Finally, SARS-CoV-2 infection induced age-dependent neuropsychiatric abnormalities including bradykinesia and obsessive-compulsive-like behavior. These observations indicate that cerebrovascular aging, including loss of Wnt suppression of Caveolin-1, heightens vulnerability to SARS-CoV-2-induced neuroinflammation and neuropsychiatric sequalae. Our work suggests that modulation of Wnt signaling or its downstream effectors at the BBB could be potential interventional strategies for Long COVID. Highlights To our knowledge, we have for the first time used a small animal model to experimentally test the impact of age on SARS-CoV-2 neuropathology. Aged mice were uniquely vulnerable to neuropsychiatric signs after SARS-CoV-2 infection Middle-age increased gliosis, cerebrovascular inflammation, BBB permeability, and T cell infiltration in SARS-CoV-2 infected mice BBB permeability was related to loss of Wnt7a suppression of Caveolin-1
Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Main subject:
Cerebrovascular Disorders
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Hypokinesia
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Lupus Vasculitis, Central Nervous System
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COVID-19
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Gliosis
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Inflammation
Language:
English
Year:
2022
Document Type:
Preprint
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