In a recent study published in the bioRxiv * prepress server, researchers at the University of Illinois at Chicago investigated whether aging exacerbated neuropsychiatric disorders induced by acute respiratory coronavirus 2 infection (SARS-CoV-2). ).
Study: Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction. Image credit: Donkeyworx / Shutterstock
Fund
The term “NeuroCOVID” encompasses the neuropathological, cognitive, and neuropsychiatric symptoms of coronavirus disease 2019 (COVID-19) and Long COVID. Post-mortem studies have shown that the brains of patients with COVID-19 die from cerebrovascular abnormalities, such as permeability of the blood-brain barrier (BBB), T-cell infiltration, gliosis, neurons, and synapse loss. .
Studies have also shown that middle-aged and elderly people are highly susceptible to NeuroCOVID. As a result, patients with COVID-19 between the ages of 36 and 65 have elevated markers of serum endothelial inflammation and neuronal injury two months after contracting mild COVID-19. Similarly, elderly COVID-19 patients also suffer from anxiety, post-traumatic stress disorder, and dementia.
BBB, which selectively restricts the permeability of central nervous system (CNS) blood vessels to macromolecules and immune cells in the blood, is damaged by the loss of endothelial junctions. Thus, age-related decrease in cerebrovascular function and BBB integrity increases susceptibility to NeuroCOVID.
About the study
In the present study, the researchers evaluated the effect of age and SARS-CoV-2 infection on BBB in vivo, hypothesizing that age-related decreases in BBB function and the site of wing-related integration (Wnt) / β-catenin aggravate NeuroCOVID. Note that Wnt / β-catenin promotes the maintenance and repair of adult BBB, and SARS-CoV-2 infection can compromise BBB.
The team inoculated intranasally into two-month-old (young) and 12-month-old (middle-aged) C57Bl / 6 mice. They used a mouse-adapted SARS-CoV-2 strain for their experiments to cause a lung infection in the test animals.
The researchers measured neurological and neuropathological outcomes in mice at the peak of viral replication in the lung, i.e., four days after inoculation (4DPI). After 4DPI, they sacrificed mice and prepared sagittal brain sections for histology. They also performed immunostaining for IV collagen of the cerebrovascular basement membrane with a 4 ′, 6-diamidino-2-phenylindole (DAPI) nuclear counterattack.
The researchers performed a reverse transcription quantitative polymerase (RT-qPCR) chain reaction for SARS-CoV-2 viral ribonucleic acid (RNA) at 4 DPI. In addition, the team measured the foci of inflammation in the BBB, the blood-meningeal barrier, and the cerebrospinal fluid barrier, and assessed the neuroanatomical distribution of T cells in the CNS.
Study results
The authors observed SARS-CoV-2 RNA in various CNS tissues, but were unable to detect viral RNA in the lungs. They also found that the molecular patterns associated with the pathogens were highly expressed in the brain after SARS-CoV-2 infection and did not vary by age.
Respiratory infection with SARS-VOC-2 causes a neuropsychiatric abnormality in middle-aged but not young adult mice. A) Mouse with new and familiar objects in the open field. B) Task of memory of recognition of new objects. Healthy young mice preferentially care for a new object (discrimination rate> 50% indicated by a horizontal dotted line). Young mice infected with SARS-CoV-2, healthy middle-aged mice, and middle-aged mice infected with SARS-CoV-2 do not prefer the new object. (n = 5-8 per group) C) There are no significant differences in total scanning time between groups (n = 5-8 per group). D) Decreased cumulative distance traveled by voluntary walking in 12-month SARS-VOC-2 mice (n = 8-9 per group). E) Speed of voluntary movement in open field (n = 8-9 per group). FG) 12-month-old infected mice have significantly increased latency in the pole descent task, a complex motor coordination task involving brainstem / thalamic connectivity (n = 5 per group). H) Duration of each spontaneous open field cleaning attack (n = 8-9 per group). I) Number of spontaneous preparation acts initiated in the open field (n = 8-9 per group). * p <0.05, ** p <0.01, *** p <0.001, **** p <0.0001, one-way ANOVA and Sidak multiple comparison test.
Robust Wnt canonical activity is needed to maintain the resilience of young adults to SARS-CoV-2 infection. BBB permeability in aged infected mice was due to the loss of Wnt3 and Wnt7a suppression of Caveolin-1, which could aggravate inflammation by enhancing the delivery of viral material through the BBB. The study data suggested that the loss of Wnt-β-catenin in the aged brain created a vulnerability to NeuroCOVID.
Caveolin-1 is a scaffold protein that promotes transcellular BBB permeability, while brainstem Zonula occludens-1 (ZO-1) is a protein that stably binds cytoskeletal binding proteins to restrict macromolecular permeability. SARS-CoV-2 infection in middle-aged mice induced the BBB Caveolin-1 transcytosis protein and reduced ZO-1. However, the infection did not cause apparent changes in the tightly bound proteins. Overall, these data indicated that age exacerbated BBB transcellular leakage caused by SARS-CoV-2 infection.
In addition, SARS-CoV-2 infection induced a two- to three-fold increase in hypercellular parenchymal foci. Compared to young mice, 12-month-old infected mice had 35 perivascular inflammatory foci per brain section and 30% more parenchymal inflammatory foci. The authors also found several inflammatory foci in the choroid plexus, which indicated SARS-CoV-2-induced parenchymal inflammation that exacerbated age.
In addition, the team observed a four-fold increase in a 3-cell (CD3) + T cell infiltration group in the brainstem and olfactory bulb in 12-month-old mice infected with SARS-CoV-2. compared to younger infected mice.
Conclusion
According to the authors, this is the first study to experimentally test the impact of age on SARS-CoV-2-induced neuropathology in a small animal model. The authors found that age worsened deregulated Wnt / β-catenin signaling and BBB permeability.
Interestingly, transcriptomic signatures of brain endothelial cells are preserved between COVID-19 and Alzheimer’s disease. In addition, cerebrovascular damage caused by SARS-CoV-2 infection could accelerate vascular cognitive impairment and dementia (VCID). Of particular concern is the fact that 1.6% of adults over the age of 65 have been diagnosed with recurrent dementia in the first three months after SARS-CoV-2 infection. In addition, it was 2.4 times more common after COVID-19 than other acute health events. In the coming years, the additive effect of the increase in neuropsychiatric diseases, including COVID-related dementia, could be surprising. In conclusion, age exacerbated BBB disruption, neuroinflammation, and neuropsychiatric presentation in SARS-CoV-2-infected mice. These findings require the identification of potential new therapeutic strategies to increase the resilience of the aging brain.
* Important news
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guided by clinical practice / health-related behavior, or treated as established information.
Magazine reference:
- Age aggravates SARS-CoV-2-induced blood-brain barrier filtration and neuropsychiatric dysfunction, Seshadri Bhargava Niladhuri, Guliz Otkiran Clare, KaReisha F. Robinson, Jacob Class, Ali A Almousawi, Troy N Trevino, Felecia Marottoli, Leon M. Tai, Justin ME Richner, Sarah E Lutz, bioRxiv prepress 2022, DOI: