Senolytics could be a beneficial treatment for COVID neuropathology

The rapid outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has sparked the coronavirus disease 2019 (COVID-19) pandemic, claiming more than 6.7 million lives worldwide . Scientists around the world are working at an unprecedented rate to understand different aspects of SARS-CoV-2, with many studies highlighting the effects of “long-lasting COVID-19” in patients previously infected with SARS-CoV. or persistent acute post-infectious syndrome (PASC) has been identified. 2.

study: Senolytic therapy mitigates physiological human brain aging and COVID-19 neuropathologyImage credit: Gorodenkoff / Shutterstock.com

Background

Common symptoms of long-term COVID include loss of taste, loss of smell, sleep disturbance, and cognitive impairment. One of the mechanisms proposed to contribute to these symptoms includes the ability of SARS-CoV-2 to infect multiple types of nerve cells and induce substantial structural changes in the patient’s brain.

Interestingly, transcriptomic profiles based on postmortem brain tissue establish strong links between cognitive decline and molecular features of brain aging in patients with severe SARS-CoV-2 infection. To this end, post-mortem biopsy reports revealed that SARS-CoV-2-infected lungs contained higher levels of senescence compared with uninfected lungs. .

Senescence is a cellular phenotype that influences organismal aging and comorbidities, especially chronic degenerative conditions. live Neuropathology models and animal studies using physiologically aged mice have revealed that senescent cells promote cognitive decline and neurodegeneration. Nevertheless, the role of senescent cells in COVID-19 pathology, particularly in human tissue brain aging and the central nervous system (CNS), remains unclear.

Brain aging is associated with cognitive decline resulting from multiple molecular processes, including inflammation and cellular senescence. This phenomenon has been established in studies on normal mouse aging and age-related neurodegeneration mouse models.

Further studies are needed to determine whether endogenous age-related initiation of cellular senescence affects human brain aging. Furthermore, it is imperative to understand whether the consequences of neurotropic viral infection accelerate the initiation of cellular senescence in the brain.

Several strategies, including pharmacological intervention, have been employed to eliminate targeted senescent cells. Several clinical trials are currently being conducted to evaluate the effectiveness of removing senescent cells using senolytic drugs.

Previous studies have demonstrated that oral administration of dasatinib and quercetin (D+Q) cocktail, or fisetin, affects blood-brain barrier (BBB) ​​permeability, thereby suggesting that these agents are associated with brain aging. It has become valuable in assessing the contribution.

About research

Recent research posted in bioRxiv* A preprint server documents the efficacy of multiple senolytic interventions in eliminating senescent cells in physiologically aged human pluripotent stem cell-derived brain organoids.

To this end, 8-month-old human brain organoids (BO) were embryonic stem cellsNewly generated BOs were exposed to two doses of senolytics for one month at two-week intervals. ABT-737, the Bcl-2 inhibitor navitoclax, and the D+Q senolytic drug cocktail were tested against BO.

Investigation result

Senolytics exposure in physiologically aged BOs showed a substantial decrease in senescence-associated β-galactosidase activity 1 (SA-β-gal) activity compared to controls. This finding indicates that all senolytic treatments were able to eliminate large numbers of senescent cells in the treated BO.

Senescent cells were found to accumulate in physiologically aged BOs of human origin. Importantly, 4-week (long-term) intermittent senolytic treatment significantly reduced inflammation and cellular senescence. Here, D+Q treatment caused anti-aging and longevity-promoting gene expression in treated BO.

Long-term senolytic therapy prevents selective accumulation of senescent cells in physiologically aged human brain organoids. Brain organoids were generated and grown in vitro 8 months, then 2 doses of either navitoclax (2.5 µM), ABT-737 (10 µM), or D+Q (D: 10 µM; Q: 25 µM) (each dose every 2 weeks) was exposed toOrganoids were then collected the following month on site analysis. (a) SA-β-gal assay was performed on organoid sections. Each data point in the bar graph represents a single analyzed organoid. Error bars represent standard deviation. At least eight individual organoids were analyzed per condition. One-way ANOVA with Tukey’s multiple comparisons post hoc correction. (B) Lamin B1 staining was performed on organoid sections. Each data point in the scatterplot represents the integrated intensity of each cell within the organoid section. At least eight individual organoids were analyzed per condition. One-way ANOVA with Tukey’s multiple comparisons post hoc correction. (CD) Representative images from quantification shown in a and b, respectively. Scale bar, 0.3 mm.

Brains of SARS-CoV-2-infected individuals showed an accelerated accumulation of cellular senescence compared with age-matched controls. It has been attributed to neurotropic viruses such as the Zika virus. Japanese encephalitis virus (JEV) and SARS-CoV-2 infect human BO and directly induce cellular senescence.

Among the emerging SARS-CoV-2 variants, the delta (B.1.617.2) variant induced the strongest cellular senescence. This observation was validated by spatial transcriptome sequencing of p16-positive cells, which detected a delta-specific senescence-associated secretory phenotype (SASP) signature.

There is an increased accumulation of p16 senescent cells in the brains of COVID-19 patients. (a) Immunofluorescence images showing DAPI (blue) and p16 (red) immunoreactivity in sections of frontal cortex regions of severe COVID-19 patients and age-matched COVID-unrelated controls. Scale bar, 50 μm. (B) Box plots indicate the percentage of p16-positive cells. Each data point in the graph represents one of her patients analyzed, with a total of 2,794,379 brain cells from seven of her COVID-19 patients and eight non-COVID-19 patients. Whiskers represent minimum and maximum values. Student’s two-tailed t-test.

A 5-day senescent cell depletion treatment of organoids infected with SARS-CoV-2 revealed a decrease in viral gene expression. Furthermore, this treatment suppressed the development of corticothalamic and GABAergic senescent neurons. Importantly, senolytic treatment following his SARS-CoV-2 intranasal infection of K18-hACE2 mice ameliorated the neuropathology of COVID-19.

Senolytic treatment enhanced clinical scores and survival rates in SARS-CoV-2-challenged mice. Increased survival of dopaminergic neurons and reduced reactive astrogliosis were also observed. Moreover, this treatment significantly reduced SASP, viral, and senescence gene expression in the brains of infected mice.

Conclusion

The current study revealed that physiologically aged human BOs accumulate senescent cells. However, senolytic treatment can effectively reduce differential SASP expression and senescent cell burden in treated BO.

Intermittent senescent cytolytic treatment improved the clinical outcome of SARS-CoV-2-infected mice, which was associated with reduced inflammation and improved survival of dopaminergic neurons.

Taken together, the current study shows that senolytic therapy can reduce long-term COVID neuropathology and other disorders caused by acute neurotropic virus infection.

*Important Notices

Bio Rxiv We publish a non-peer-reviewed, preliminary scientific report and should not be taken as conclusive, to guide clinical practice/health-related actions, or to be treated as established information.