Role of aging in Blood–Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: impacts on neurological symptoms of COVID-19

Abstract

COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. The blood–brain barrier (BBB) was suggested to be the major route of SARS-CoV-2 infection of the brain. Functionally, the BBB is created by an interactome between endothelial cells, pericytes, astrocytes, microglia, and neurons, which form the neurovascular units (NVU). However, at present, the interactions of SARS-CoV-2 with the NVU and the outcomes of this process are largely unknown. Moreover, age was described as one of the most prominent risk factors for hospitalization and deaths, along with other comorbidities such as diabetes and co-infections. This review will discuss the impact of SARS-CoV-2 on the NVU, the expression profile of SARS-CoV-2 receptors in the different cell types of the CNS and the possible role of aging in the neurological outcomes of COVID-19. A special emphasis will be placed on mitochondrial functions because dysfunctional mitochondria are also a strong inducer of inflammatory reactions and the “cytokine storm” associated with SARS-CoV-2 infection. Finally, we will discuss possible drug therapies to treat neural endothelial function in aged patients, and, thus, alleviate the neurological symptoms associated with COVID-19.

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

“…Interestingly, extensive perivascular leukocyte cuffing reportedly occurs only in a subset of COVID-19 decedents, suggesting that individual risk factors contribute to CNS presentation of infection (Agrawal et al, 2022; Thakur et al ., 2021). Individual risk factors related to Cav-1 and other regulators of BBB adhesion and permeability may modify leukocytic infiltration and neurologic symptoms of SARS-CoV-2 infection (Adesse et al, 2022; Iadecola et al, 2020; Monje and Iwasaki, 2022; Teuwen et al, 2020; Vanderheiden and Klein, 2022; Vavougios et al, 2022).…”

The role of the blood–brain barrier during neurological disease and infection

“…BBB damage due to inflammation is a final common pathway in many brain infections as well, allowing pathogens and immune cells access to the brain, and leading to CNS damage. For example, an inflammatory cytokine-mediated pathway is implicated for the BBB disruption seen in encephalitis caused by viruses such as Japanese encephalitis virus ( JEV) [51,95], herpes simplex virus (HSV) [52,53], West Nile virus (WNV) [96,97] and human immunodeficiency virus (HIV) [98,99] and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [56,100]. Several studies have provided evidence for an important role for inflammation in BBB BBB disruption is implicated in many neurological infections and diseases, including neurodegenerative diseases, ischaemic stroke as well as viral infections such as SARS-CoV-2, and peripheral diseases such as atrial fibrillation.…”

Long COVID in the context of social determinants of health

“…Multiple attempts have been made to identify vulnerable populations by examining the predictors of risk of infection and the severity of COVID-19. The following factors were identified as potential contributors to the disparity in exposure to the infection, morbidity, and mortality of COVID-19: race/ethnic differences, older age, living with multiple chronic conditions, genetic differences in Human Leukocyte Antigen (HLA) alleles, low socioeconomic status, and limited access to care (28)(29)(30)(31).…”