Study: Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction. Image Credit: Donkeyworx / Shutterstock

Age exacerbates neuroimmunological symptoms of COVID

In a recent study published on bioRxiv* preprint server, researchers at the University of Illinois at Chicago investigated whether aging exacerbates neuropsychiatric disorders induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study: Age exacerbates SARS-CoV-2-induced blood-brain barrier leakage and neuropsychiatric dysfunction. Image Credit: Donkeyworx/Shutterstock

Background

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 deceased COVID-19 patients have cerebrovascular abnormalities, including permeability of the blood-brain barrier (BBB), T cell infiltration, gliosis, neurons and synapse losses.

Likewise, studies have shown that middle and older aged people are highly susceptible to NeuroCOVID. Accordingly, COVID-19 patients between the ages of 36 and 65 have elevated markers of endothelial inflammation and neuronal injury in their serum two months after contracting mild COVID-19. Similarly, older COVID-19 patients also suffer from anxiety, post-traumatic stress disorder, and dementia.

The BBB, which selectively limits the permeability of central nervous system (CNS) blood vessels to macromolecules and blood immune cells, is damaged by loss of endothelial tight junctions. Thus, age-related decline in cerebrovascular function and BBB integrity increases susceptibility to NeuroCOVID.

About the study

In the current study, researchers assessed the effect of age and infectious SARS-CoV-2 on the BBB live, hypothesizing that age-related declines in BBB function and the wingless (Wnt)/β-catenin integration site exacerbate NeuroCOVID. Note that Wnt/β-catenin promotes BBB maintenance and repair in adults, and SARS-CoV-2 infection can compromise BBB.

The team intranasally inoculated two-month-old (young) and 12-month-old (middle-aged) C57Bl/6 mice. They used a mouse-adapted strain of SARS-CoV-2 for their experiments to cause lung infection in test animals.

The researchers measured neurological and neuropathological outcomes in mice at the peak of viral replication in the lungs, i.e. four days after inoculation (4DPI). After 4DPI, they euthanized mice and prepared sagittal brain sections for histology. They also performed immunostaining for cerebrovascular basement membrane collagen IV with 4′,6-diamidino-2-phenylindole (DAPI) nuclear counterstain.

The researchers performed quantitative reverse-transcription polymerase chain reaction (RT-qPCR) for SARS-CoV-2 viral ribonucleic acid (RNA) at 4 DPI. Additionally, the team measured foci of inflammation in the BBB, blood-brain barrier and blood-cerebrospinal barrier and assessed the neuroanatomical distribution of T cells in the CNS.

Study results

The authors observed SARS-CoV-2 RNA in several CNS tissues but could not detect viral RNA in the lungs. They also found that pathogen-associated molecular patterns were highly expressed in the brain after SARS-CoV-2 infection and did not differ by age.

SARS-COV-2 respiratory infection causes neuropsychiatric abnormality in middle-aged mice but not in young adults.  A) Mouse with new and familiar objects in an open field behavior arena.  B) New object recognition memory task.  Healthy young mice preferentially attend to the novel object (discrimination index >50% indicated by a dashed horizontal 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 novel object.  (n=5-8 per group) C) No significant difference in total exploration time between groups (n=5-8 per group).  D) Decreased cumulative distance traveled by voluntary ambulation in 12-month-old SARS-COV-2 mice (n=8-9 per group).  E) Voluntary movement speed in the open field (n=8-9 per group).  FG) infected 12-month-old 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 field grooming episode (n = 8-9 per group).  I) Number of spontaneous grooming episodes initiated in the field (n = 8-9 per group).  *p<0.05, **p<0.01, ***p<0.001, ****p<0,0001, ANOVA unidirectionnelle et test de comparaisons multiples de Sidak.

SARS-COV-2 respiratory infection causes neuropsychiatric abnormality in middle-aged mice but not in young adults. A) Mouse with new and familiar objects in an open field behavior arena. B) New object recognition memory task. Healthy young mice preferentially attend to the novel object (discrimination index >50% indicated by a dashed horizontal 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 novel object. (n=5-8 per group) C) No significant difference in total exploration time between groups (n=5-8 per group). D) Decreased cumulative distance traveled by voluntary ambulation in 12-month-old SARS-COV-2 mice (n=8-9 per group). E) Voluntary movement speed in the open field (n=8-9 per group). FG) infected 12-month-old 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 field grooming episode (n = 8-9 per group). I) Number of spontaneous grooming episodes initiated in the field (n = 8-9 per group). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, one-way ANOVA and Sidak's multiple comparison test.

Robust canonical activity of Wnt is required to maintain the resilience of young adults to SARS-CoV-2 infection. BBB permeability in aged infected mice was due to loss of caveolin-1 deletion of Wnt3 and Wnt7a, which may exacerbate inflammation by enhancing delivery of viral material through the BBB. Data from the study suggests that loss of Wnt-β-catenin in the aging brain creates vulnerability to NeuroCOVID.

Caveolin-1 is a scaffolding protein that promotes BBB transcellular permeability, while brainstem Zonula occludens-1 (ZO-1) is a protein that stably links junctional proteins to the cytoskeleton to limit permeability macromolecular. SARS-CoV-2 infection in middle-aged mice induced down-regulated BBB Caveolin-1 and ZO-1 transcytosis protein. However, the infection did not cause any apparent changes in the tight junction proteins. Taken together, these data indicated that age exacerbates BBB transcellular leakage caused by SARS-CoV-2 infection.

Furthermore, SARS-CoV-2 infection induced a two- to three-fold increase in parenchymal foci of hypercellularity. Compared to young mice, infected 12-month-old mice had 35 perivascular inflammatory foci per brain section and approximately 30% more parenchymal inflammatory foci. The authors also found a few inflammatory foci in the choroid plexus, indicating age-exacerbated SARS-CoV-2-induced parenchymal inflammation.

Additionally, the team observed a four-fold increase in a cluster of differentiation 3 (CD3)+ Brainstem and olfactory bulb T cell infiltration in 12-month-old mice infected with SARS-CoV-2 compared with 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 demonstrated that age worsened the dysregulation of Wnt/β-catenin signaling and BBB permeability.

Curiously, the transcriptomic signatures of brain endothelial cells are conserved between COVID-19 and Alzheimer’s disease. Additionally, cerebrovascular damage caused by SARS-CoV-2 infection could accelerate vascular cognitive impairment and dementia (VCID). Of particular concern is that 1.6% of adults over the age of 65 were diagnosed with new-onset dementia within the first three months of SARS-CoV-2 infection. Additionally, it was 2.4 times more common after COVID-19 than other acute health events. In the years to come, the additive effect of the increase in neuropsychiatric illnesses, including COVID-related dementia, could be staggering. To conclude, age worsened BBB disruption, neuroinflammation and neuropsychiatric presentation in SARS-CoV-2 infected mice. These findings necessitate the identification of potential new therapeutic strategies to increase the resilience of the aging brain.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

Journal reference:

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