SARS-CoV-2 can reach the CNS via the olfactory tract ^[1][84]. The human olfactory epithelium is a pseudostratified epithelium composed of Bowman’s glands, horizontal and globose basal cells, microvillar cells, sustentacular cells, and olfactory sensory neurons that extends a single axon towards the olfactory bulb in the brain. Sustentacular cells in the olfactory epithelium exhibit high levels of ACE2 and TMPRSS2 ^[2][75] and a study in hamsters showed SARS-CoV-2 active infection in those cells ^[3][85]. In agreement, autopsies of COVID-19 patients revealed that the olfactory sensory epithelium was severely damaged ^[2][75]. Despite the absence of ACE2 and TMPRSS2 in the olfactory sensory epithelium, the olfactory nerve tissue was found to be positive to SARS-CoV-2 in post-mortem examinations of COVID-19 patients ^[4][86]. Thus, it is possible that the replication of virions in the olfactory epithelium leads to infection in the olfactory bulb as blood vessels and pericytes in this brain region express both proteins ^[5][6][87,88]. These neurotrophic properties of SARS-CoV-2 explain the onset of anosmia as a prior symptom ^[7][89]. Interestingly, in mice, ACE2 and TMPRSS2 expression in the olfactory epithelium increases with age ^[2][8][75,90], suggesting a possible mechanism by which older patients are more vulnerable to the disease and neurological complications.

Furthermore, the virus can reach brain tissue by the hematogenous route, in which endothelial cells or leukocytes are infected by the virus that passes from the bloodstream to the CNS ^[2][75] across the blood–brain barrier (BBB) ^[9][10][91,92] or by transmigration of peripheral immune cells, following the “Trojan horse” mechanism ^[11][12][93,94]. For example, brain vascular cells and choroidal barrier cells robustly express several genes that are relevant for SARS-CoV-2 entry into the brain ^[13][95]. SARS-CoV-2 infects and crosses an in vitro model of the BBB comprising primary brain microvascular endothelial cells and astrocytes ^[14][96]. Infection of ACE2-overexpressing primary human endothelial cells by SARS-CoV-2 induces the overexpression of coagulation factors, adhesion molecules, and pro-inflammatory cytokines, as well as the formation of multinucleated syncytia and endothelial cell lysis ^[15][97]. Consequently, SARS-CoV-2 alters the function and integrity of the BBB, which contributes to viral encephalopathy ^[16][17][98,99].

Furthermore, ACE2 receptors have been found in glial cells of the brain and spinal neurons, so SARS-CoV-2 can adhere, multiply, and cause direct damage to neuronal tissue ^[18][100]. Neuronal infection has been associated with neurodegeneration and neurovascular remodeling ^[19][101], causing cerebral vascular/endothelial dysfunctions that can generate cerebral circulatory disturbances ^[20][102]. Helms et al., using perfusion imaging, demonstrated in patients with COVID-19 that SARS-CoV-2 neuroinvasion causes bilateral frontotemporal hypoperfusion, demonstrating cerebral circulatory impairment ^[21][103]. As consequences of cerebral hypoxia, COVID patients can show cerebral vasodilation, brain cell swelling, interstitial edema, obstruction of cerebral blood flow, and even headache due to ischemia and congestion ^[22][104].

Exacerbated inflammation participates in the damage to nervous tissue, as in other target organs. SARS-CoV-2 elicits an exacerbated and deregulated immune response of soluble immune mediators, termed a “cytokine storm” ^[23][105]. Multiple immune mediators, such as IL-1β, IL-6, CXCL10, TNFα, and other diverse cytokines are produced in response to SARS-CoV-2 infection and have been associated with functional alterations or tissue damage in different organs, including the brain ^[24][106].

In addition, elevated levels of pro-inflammatory cytokines could participate in aggravating neuropathies during critical COVID-19 illness. The overproduction of systemic inflammatory factors (cytokines, nitric oxide, and oxygen radicals) has been associated with the malfunction of peripheral nerves ^[25][107] as well as microvascular disorders and electrical and metabolic (channel) disturbances in muscle cells ^[26][108].

In addition, chronic damage to other systems can also damage the CNS through ischemia, metabolic dysfunction, and hormonal dysregulation ^[27][109]. Coagulopathy and endotheliopathy triggered by cytokine storms are potential mechanisms causing ischemic stroke in COVID-19 patients ^[28][29][110,111]. Furthermore, COVID-19 patients have elevated levels of von Willebrand factor (VWF) antigen, VWF activity, and factor VIII ^[30][112], leukocytosis, thrombocytopenia, increased partial thromboplastin time, and low levels of antithrombin activity ^[31][113]. COVID-19 patients are at an increased risk of developing venous thromboembolism and disseminated intravascular coagulation ^[32][114].

Cerebral venous sinus thrombosis (CVT) can be caused by the hypercoagulable state in SARS-CoV-2 infection, which may be triggered by endothelial dysfunction that predisposes vessels to thrombus formation, platelet dysfunction, hypoxia, and/or alterations of the complement system ^[33][34][115,116]. CVT may cause generalized neurological deficits ^[35][117] and there are multiple reports of its association with SARS-CoV-2 infection ^[36][37][118,119].

Moreover, the renin-angiotensin-aldosterone system (RAAS) can contribute to the appearance of brain damage and systemic hyperinflammatory state in COVID-19 patients ^[38][39][120,121]. It has been reported that during SARS-CoV-2 infection: (1) the local levels of angiotensin II (Ang II) increase, acting on angiotensin II type 1 receptors (AT1), and thus increasing arterial pressure; (2) there is endothelial dysfunction in the cerebral vessels in the CNS, which increases the risk of cerebral hemorrhage; and (3) the generation of Ang (1–7) decreases, preventing the vasodilator, neuroprotective, and antifibrotic effects of Ang (1–7)/Mas receptor signaling ^[40][41][122,123].

An overproduction of reactive oxygen species (ROS) and the deprivation of antioxidant mechanisms are known to be crucial for viral replication and subsequent virus-associated disease, as shown by increased ROS levels and impaired antioxidant defense during SARS-CoV-2 infection ^[42][124]. The viral protease Mpro activates nuclear factor kappa B (NF-kB)-mediated transcription, which correlates with increased levels of intracellular ROS ^[43][125]. In addition, Mpro causes a significant increase in ROS production in HL-CZ cells, which, in turn, induces cellular apoptosis. Similarly, SARS-CoV-2 increases oxidative stress in nervous tissue, which contributes to neuronal cell death ^[44][45][126,127]. A post-mortem case study showed that 37 of 43 COVID-19 patients had astrogliosis and 34 had microglial activation in the brainstem and cerebellum ^[46][128]. In a preclinical trial, neuronal microgliosis in the brain has been observed to persist beyond SARS-CoV-2 clearance ^[47][129].

Protein misfolding and aggregation have also been reported in COVID-19. Interactions between the S protein of SARS-CoV-2 and its receptor ACE2 favor the spread of cytosolic prions and tau aggregates ^[48][130]. The RBD domain of the S1 subunit from SARS-CoV-2 S protein (RBD SARS-CoV-2 S1) binds heparin and heparin-binding proteins, accelerating the pathological aggregation of brain proteins, including Aβ (amyloid beta), α-synuclein, tau, prion, and TDP-43 RRM ^[49][131]. In addition, SARS-CoV-2-infected hamsters develop microgliosis in the olfactory bulb and selective accumulation of hyperphosphorylated tau and α-synuclein in the cortex after virus clearance, indicating that proteinopathies can be generated in neurons post-infection ^[47][129]. Although further studies are required, this evidence suggests that protein misfolding may play a role in the neurological symptoms caused by SARS-CoV-2 infection.

Neurotrophins are growth factors acting as regulators of neuronal survival, development, function, and plasticity ^[50][132]. Neurotrophins include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) ^[51][133]. In addition to their classical functions, they regulate axonal and dendritic growth and guidance, synaptic structure and connections, neurotransmitter release, and long-term potentiation, a cellular mechanism underlying memory and learning ^[52][134]. The circulating levels of BDNF ^[53][135] and NGF ^[54][136] are reduced in adult COVID-19 patients compared to healthy individuals. BDNF reduction is higher in patients > 60 years of age ^[55][137], indicating age-dependent effects. Reductions in serum BDNF correlate with the severity of the disease ^[55][56][137,138] and cognitive impairment after recovery ^[57][139]. Interestingly, adult COVID-19 patients that required supplemental oxygen had even lower BDNF serum concentrations ^[53][135], showing an interplay between deregulated BDNF levels and viral hypoxia. These findings support the role of neurotrophins in regulating neurological outcomes in COVID-19 patients. However, further studies are required to define the extent of their participation and the mechanisms involved, especially in the long-lasting effects of this disease.