Fig. 2

The aged brain, neuroinflammation, and the impact of SARS-CoV-2. (A) Aging, peripheral immunosenescence, and inflammaging induce age-related changes in the blood. Chronic exposure to pro-inflammatory factors may disrupt the endothelial barrier and allow the unhindered transfer of immune cells and pro-inflammatory cytokines into the brain parenchyma, activating microglia and driving low-grade brain inflammation. Activated microglia and astrocytes produce further inflammatory mediators. Protective M-2 macrophages turn into pro-inflammatory M1-phenotype and contribute to further neuroinflammation. An inflammatory environment disrupts the delicate balance needed for LTP-induction, impairs synaptic plasticity, and downregulates the production of BDNF and IGF-1. This leads to negative consequences for neural precursor cells decrease and for the normal neuronal functioning. (B) Aging, stress, and inflammaging activate the HPA axis to release CRH from the paraventricular nucleus and trigger the anterior pituitary gland to secrete ACTH. This stimulates the release of glucocorticoids from the adrenal gland into the circulation. High concentrations of cortisol can, in turn, impair hippocampal neurogenesis. (C) Infection with SARS-CoV-2 may be an additional immune stressor, contributing to an elevated neuroinflammatory markers and resulting in more intense and unremitting immune reactions. The SARS-CoV-2-induced astro- and microgliosis contributes to BBB-disintegration and elevated levels of pro-inflammatory cytokines and is associated with neuronal loss. These combined effects may lead to symptomatic exacerbation, neurodegeneration, and a perpetuation of functional decline

Abbreviations: SARS-CoV-2: Severe acute respiratory syndrome coronavirus type 2; HPA: Hypothalamic-pituitary-adrenal axis; CRH: corticotropin releasing hormone; ACTH: adrenocorticotropin; IL: interleukin; IFN: interferon; TNF: tumor necrosis factor; LTP: long term memory potentiation; BDNF: brain-derived neurotrophic factor; IGF: insulin-like growth factor. Modified from [2].