Fig. 4

Summary of potential mechanisms involved in the pathogenesis of neurological symptoms in the spectrum of long COVID. Neurological symptoms in long COVID may be attributed to two main mechanisms: viral neuro-invasion and persistent neuroinflammation. The SARS-CoV-2 virus interacts with angiotensin-converting enzyme 2 (ACE2) receptors present not only in the lungs but also in neural cells. One potential route for the virus to enter the central nervous system is through endothelial transcytosis. Notably, the brainstem harbors a significant number of ACE2 receptors, which may account for autonomic dysregulation observed in long COVID patients [46]. Furthermore, patients with neurological symptoms who have recovered from COVID-19 exhibit structural and metabolic brain abnormalities [47,48,49]. These findings suggest that persistent neuroactivation is a consequence of immunological overactivation triggered by upregulated expression of proinflammatory cytokines such as IFN-β, IFN-λ1, IFN-γ, IL-2, IL-6, IL-17, CXCL8, CXCL9, and CXC10. This immune response activates non-classical and intermediate monocytes, fibroblasts, and myeloid cells while also inducing a dysfunctional T_H2 cytokine pool that produces CCL11. These pathways collectively result in microglia activation, leading to subcortical white matter demyelination by damaging oligodendrocytes and their precursors, as well as diminished hippocampal neurogenesis. Additionally, T-cell dysfunction and monocyte expansion may contribute to chronic inflammation and disruption of the blood-brain barrier [43]