Abstract
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the pulmonary manifestations, COVID-19 patients may present a wide range of neurological disorders as extrapulmonary presentations. In this view, several studies have recently documented the worsening of neurological symptoms within COVID-19 morbidity in patients previously diagnosed with neurodegenerative diseases (NDs). Moreover, several cases have also been reported in which the patients presented parkinsonian features after initial COVID-19 symptoms. These data raise a major concern about the possibility of communication between SARS-CoV-2 infection and the initiation and/or worsening of NDs. In this review, we have collected compelling evidence suggesting SARS-CoV-2, as an environmental factor, may be capable of developing NDs. In this respect, the possible links between SARS-CoV-2 infection and molecular pathways related to most NDs and the pathophysiological mechanisms of the NDs such as Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis will be explained.
Introduction
Pandemic COVID-19 is caused by SARS-CoV-2, structurally a large enveloped non‐segmented positive‐sense RNA virus [1]. This virus, along with its spike protein (S), makes contact with cells and binds to several host proteins (known as virus receptors) that assist in its entry into cells [1]. After entry into the host cell, viral pneumonia (fever, cough, dyspnea, hypoxemia) [2–5], acute tubular necrosis (loss of brush border, vacuolar degeneration, luminal dilatation) [6], and gastrointestinal manifestations (diarrhea, diminished appetite, nausea, vomiting, abdominal pain) [4, 7] are commonly seen in humans. The expression of specific receptors is necessary for SARS-CoV-2 binding and entering the target cells. In this regard, CD147, a member of the immunoglobulin superfamily was a suggested receptor that plays a role in virus binding [8]; however, newer studies have ruled out the role of this transmembrane glycoprotein [9]. Following SARS-CoV-2 binding, an androgen‐responsive serine protease, namely transmembrane protease serine 2 facilitates virus entry and activation by cleavage of the virus S protein. This protease is highly expressed in epithelial cells of the respiratory, gastrointestinal, urogenital tract, and brain cell lines [10]. In addition, it has been shown that angiotensin-converting enzyme 2 (ACE2) is the main protein responsible for the cellular accumulation of SARS-CoV-2 [11–13]; this is an enzyme that converts angiotensin II to angiotensin and is distributed throughout the body and the brain. In the brain, ACE2 is expressed both on neurons and glial cells and on endothelial and arterial smooth muscle cells. ACE2 is also expressed in different central nervous system (CNS) compartments such as the temporal lobe and hippocampus [14]. Its expression can be enhanced by cytokines, such as interferon [15] or other inflammatory responses [16], and maybe regulated by excitotoxicity [17]. Also, it has been reported that heparan sulfate proteoglycans (HSPGs) can facilitate virus binding to the receptor ACE2 [18].
Altogether, the data mentioned illustrate that SARS-CoV-2, capable of infecting the brain and the nervous system, can present nervous system symptoms in COVID-19 patients. SARS-CoV-2, due to its spread to the brain through the olfactory route [19], the hematogenous route [20] and the enteric-vagal routes [21] is associated with a variety of other symptoms and clinical manifestations [2], such as dysfunction of the central (fatigue, headache, confusion, stroke [22], dizziness, syncope [23], seizure, anorexia, and insomnia [24–27]), peripheral (anosmia, ageusia, myoclonus [28], neuropathic pain, and myalgias) [5, 24, 29]) combined central-peripheral (Guillain Barre syndrome [30]) and enteric nervous systems (diarrhea [31]). It has been documented that SARS-CoV-2 enters CNS via ACE2 receptors present on brain endothelial cells, which constitute the blood-brain barrier (BBB). Subsequently, reduction in tight junction protein gene expression levels in endothelial cells would be induced, which leads to alteration in BBB integrity and permeability, resulting in neuro-invasion of SARS-CoV-2 and neuroinflammatory responses [32–34].
A broad spectrum of neurological diseases has been categorized as neurodegenerative diseases (NDs). The activation of glial cells and the following related happenings, as inflammatory responses, are categorized as a set of the underlying mechanisms of this kind of disease [35]. Likewise, an increase in proinflammatory cytokines and consequent neuroinflammation can also be associated with SARS-CoV-2 infection. Also, several studies have recently documented the worsening of neurological symptoms within COVID-19 morbidity in patients previously diagnosed with NDs. These mentioned documentations under the shadow of the history of controversial relation between the post-infectious detected encephalitis lethargica and NDs raise a major concern about the possible role of SARS-CoV-2 infection in triggering and/or exacerbating the well-known NDs such as Alzheimer's disease (AD) and Parkinson's disease (PD). Accordingly, this paper tries to explain this possible role based on the ability of SARS-CoV-2 infection in inducing neuropathogenic alterations similar to those explicitly observed in different human NDs. Section “Coronavirus-mediated neuropathogenesis” details the possible pathways that may lead to nerve degeneration due to COVID-19, and the pathways documented in this section can be common to all neurodegenerative diseases. However, afterward, in Section “The possible interactions…”, the pathways that may be specifically associated with developing the well-known neurodegenerative disease mentioned in each subsection are stated.
History of the link between viruses and neurodegenerative diseases
The destructive effect on the nervous system is not limited to SARS-CoV-2 infection. Previous studies have shown that some viruses associated with different types of NDs can injure neurons by gaining access to neurons through the BBB system, causing cell lysis and neuronal death. In this regard, it has been reported that there is a link between human immunodeficiency viruses and dementia [36], in which the death of neurons is caused by inflammation and apoptosis [37]. On this line, based on the pertinent studies, the influenza virus can produce neurodegenerative diseases such as PD, one of the progressive neurological disorders [38]. The Austrian physician von Economo described a peculiar condition, postencephalitic parkinsonism, which was controversially ascribed to the influenza pandemic between 1916 and 1929. This condition is associated with movement, psychiatric and sleep disorders, and results from a post-infectious and/or autoimmune process [39]. Several research studies have also proposed neurological complications, such as PD to be a sequela of influenza infection [40, 41]. In addition, it has been shown that the Epstein–Barr virus has a major role in inflammation and neurodegeneration, which can cause multiple sclerosis and encephalitis [42, 43]. The documentations mentioned above accentuate the link between viruses and CNS damage, which can result in neurodegeneration. Thus, it is essential to deepen our knowledge about the influence of viruses on the progression of NDs, which represent a significant burden to human health worldwide. In the following sections, the possible effects of the virus SARS-CoV-2 on the progression of NDs will be discussed.
Coronavirus-mediated neuropathogenesis
Regardless of the disease type, this section points out the possible pathways that may lead to nerve degeneration due to COVID-19, and the pathways demonstrated in this section can be common to all neurodegenerative conditions.
Based on the pertinent studies, SARS-CoV-2 can bring about a hyper-inflammatory condition through its interaction with macrophages, microglia, and astrocytes in the CNS and the subsequent release of cytokines [44]. Such status can give rise to increased BBB permeability, cerebrovascular endothelial dysfunction, and BBB destruction, which eventuates to the entrance of more inflammatory factors into the CNS, leading to neurological disorders and neurodegenerative diseases [32, 33, 45–60].
In addition, SARS-CoV-2 can induce or inhibit various mitochondrial processes [61], leading to exacerbated and uncontrolled oxidative stress, which hampers the optimal functioning of cells such as neurons [62–65], resulting in NDs [66–68]. Also, in SARS-CoV-2 infected patients, misfolded protein aggregation and endoplasmic reticulum (ER) stress have occurred, which have major roles in ND progression. Protein folding is a process in which a proper 3D structure is formed in the ER, which can be disrupted, resulting in misfolded protein aggregation and ER stress by several external factors such as toxic substances, ischemia, and oxidative stress and several internal factors such as the production of truncated proteins caused by genetic abnormalities. ER stress and the subsequent adaptive cellular responses are known as the unfolded protein response (UPR). The chaperone BiP engages misfolded proteins and their segregation from IRE1, PERK, and ATF6 complex ER, which gives rise to the activation of these proteins [69, 70]. Each of the mentioned proteins is capable of mediating UPR through the parallel signaling pathways, which can eventually promote the production of cytoprotective molecules such as molecular chaperones in ER, as well as reduce the burden of newly synthesized unfolded proteins on ER by the suppression of the protein translation, and potentiating the degradation rate of misfolded proteins [69]. Although the UPR has protective results for cells, in response to an excessive load of misfolded proteins such as that associated with higher viral load, prolonged UPR may have uncompensated outcomes. In this view, high/chronic ER stress may also promote cell death by degradation of the antiapoptotic proteins' mRNAs mediated by IRE1 [71, 72]. The activation of IREα can cause the decay of select microRNAs, which normally have a role in repressing the translation of caspase-2 mRNA. Therefore, IRE1 activity can reraise the protein levels of Casp-2, which initiates the mitochondrial apoptotic pathway [73–75]. Under persistent ER stress, the influx of Ca2+ into mitochondria may happen following the outflow of Ca2+ from ER. This can also lead to apoptotic cell death by activating caspase-9 and -3 [76, 77]. Furthermore, PERK activation results in expressing ATF4 and producing the transcription factor C/EBP homologous protein (CHOP), which can induce the downregulation of Bcl-2 and lead to apoptosis [78]. In addition, it has been demonstrated that IRE1 and ATF6 also mediate the proapoptotic activity of CHOP in the CNS in ER stress [79, 80]. On the other hand, the catabolic process, autophagy, has been shown to have a prominent role in cell survival. However, its excessive activation is thought to lead to cell death [81, 82]. In this way, the interplay between ER stress signaling and autophagy has been suggested in NDs. Accordingly, different ER stress-related signaling branches such as IRE1-sXBP1 and PERK-elf2α arms probably play a role in developing NDs through the interaction with several autophagy-related proteins [83, 84]. Furthermore, the IFN-γ–stimulated ATF6–C/EBP-β–signaling pathway also induces autophagy [85]. In addition, it has been suggested that ER stress signaling also has a potential role in CNS-associated neuroinflammation and the development of NDs [86]. In NDs such as AD and amyotrophic lateral sclerosis (ALS), the destructive role of a subset of molecularly characterized microglia, namely disease-associated microglia, has been recognized [86, 87]. Interestingly, it has been shown that in microglia, ATF6α has a regulatory effect on the NF-κB-mediated inflammatory response, which in turn postulates the role of ER stress signaling in the regulation of inflammatory response in the CNS [88]. Several lines of studies have demonstrated that coronaviruses actuate ER stress. The overexpression of SARS-CoV-2 S protein can induce all three branches of UPR resulting from the activation of IRE1, PERK, and ATF6. In parallel, ORF8, a rapidly evolving accessory protein of SARS-CoV-2, can activate both the IRE1α and ATF6 UPR branches [89]. Moreover, through the common nsp2 interactors, this virus can be involved in ER calcium signaling [90]. Accordingly, SARS-CoV-2 is considered a factor capable of inducing neurodegeneration and neuronal cell death by induction of UPR and ER stress [69, 91] (shown in Fig. 1). Regarding pathophysiological mechanisms of NDs such as PD, the interactions between environmental and genetic factors activate molecular events resulting in the progression of such diseases [92]. Therefore, the accumulation of misfolded proteins and ER stress are noticeable events in NDs progression (Aoe T. 2020).
Schematic figure showing the calcium outflow, PERK, IRE1, ATF6 associated signaling pathways within a neuron which possibly lead to the development of neurodegeneration under the effect of SARS-CoV-2. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 [69, 89–91, 95]
Citation: Physiology International 109, 2; 10.1556/2060.2022.00019
Considering the ER stress-inducing effect of SARS-CoV-2 and the role of ER stress in the progression of NDs [93] through the promotion of neurotoxicity by activating inflammation and apoptosis [94] and autophagy [95] (shown in Fig. 1), it is suggested that this virus, as an environmental factor, may be capable of triggering and/or exacerbating the NDs in individuals associated with predisposing factors such as genetic makeup. This is a possibility that may result in neurodegeneration in an overall view.I In the following sections, we will discuss specific NDs in which the SARS-CoV-2 infection may relate to their underlying pathophysiological mechanisms.
The possible interactions of coronavirus with neurodegenerative diseases
The previous section, section “Coronavirus-mediated neuropathogenesis”, indicated the possible pathways that may lead to nerve degeneration due to COVID-19, which can be common to all neurodegenerative conditions. Nonetheless, in this section, the pathways that may be significantly associated with developing the well-known neurodegenerative diseases are detailed.
Alzheimer's disease (AD)
AD is the most common form of dementia which gradually progresses caused by the degeneration of the cells in the brain, leading to the progressive alteration of several functions, such as difficulty in remembering recent events [96]. As the disease advances, patients can have problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues [97]. Following that, slowly, functions of the body are lost, leading to death at last. It has been shown that AD's pathology is associated with amyloid-beta (Aβ) plaques [98–100], tau proteins [101], neurofibrillary tangles (NFT) [102], reduced levels of dopamine (DA) and its receptors [103–105], glial hypertrophy, myelin disruption [106], the loss of neuronal connections [107], neuronal death, and oligodendroglial degeneration in the brain.
The possible link between SARS-CoV-2 infection and the development of AD
The connection between COVID-19 and AD is unclear, but literature reports of cognitive and memory impairment after COVID-19 have been documented. In this view, 30–40% of patients reported problems with memory four months after COVID-19 hospitalization [108]. Likewise, younger individuals are at risk for COVID-19-related cognitive symptoms, even without the severe disease. Also, it has been shown that SARS-CoV-2 may actually induce memory loss eight months after having a mild case of the condition [109]. Moreover, several evidence shows that SARS-CoV-2 infection has a possible impact on developing AD. In this respect, ACE2, the main protein responsible for the cellular accumulation of SARS-CoV-2 may be expressed in the temporal lobe and hippocampus, representing cerebral regions involved in the pathogenesis of AD [14]. Furthermore, it has been shown that SARS-CoV-2 has a possible role in AD underlying pathophysiology such as Aβ plaques and tau proteins. In this view, the significant increasing effect of this virus on phosphorylation of the tau protein has been detected in infected brain organoids [110]. The tau protein is a phosphoprotein expressed in the axon of neurons, which promotes microtubule assembly and plays a role in maintaining neuronal integrity and axonal transport [111, 112]. Tau pathology and its intracellular aggregation, which results from tau detachment from the microtubules can be developed by hyperphosphorylation induced by the activation of several kinases such as glycogen-synthetase kinase 3 b, cyclin-dependent kinase 5 and cdc2 protein kinase, mitogen-activated kinase including extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38 MAP kinase [113]. This, in turn, induces filamentous lesions in neurons and sometimes in glia which are sufficient to cause tauopathies (a heterogeneous group of NDs) such as AD [114]. Also, this virus plays a role in the accumulation of Aβ. Aβ is the main component of amyloid plaques which are the extracellular deposits found in the brains of people with AD, produced by activating secretase family enzymes. It has been reported that the inhibition of secretases and kinases is caused by ACE2-related pathways, and the process of inhibiting these signaling pathways can be caused by the COVID-19 virus resulting in long-term neurological sequels following the activation of AD triggering signaling pathways [115] (shown in Fig. 2). Moreover, oxidative stress induced by SARS-CoV-2 can lead to Aβ accumulation. In this regard, glutamine synthetase (GS) is an enzyme that interacts with Aβ and prevents Aβ fibrillogenesis, the process by which a peptide forms insoluble aggregates of amyloid. However, following oxidative stress, GS activity is inhibited, leading to structural alteration of the enzyme. This alteration can prevent the GS-induced modification effect on the fibrillogenic and toxicologic properties of Aβ, playing a pivotal role in neurotoxicity in the AD brain [116–118] (shown in Fig. 2). Based on SARS-CoV-2-induced uncontrolled oxidative stress, it can be considered that SARS-CoV-2 infection may have a role in aggregating Aβ in this way. Overall, since tau protein and Aβ aggregation are the pathophysiological mechanisms in AD and regarding the effect of SARS-CoV-2 infection on increased phosphorylation of tau [110] and Aβ, it can be suggested that SARS-CoV-2 infection may have a role in inducing and intensifying AD. This possible effect will be elucidated in the clinic in the coming times.
Schematic figure explaining pathways that result in neurodegenerative diseases via SARS-CoV-2: (a) The interaction of SARS-CoV-2, ACE2 receptor, and GS enzyme leading to the development of AD and FTD. ACE2, angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; GS, glutamine synthetase; AD, Alzheimer's disease; FTD, Frontotemporal disorder [110, 115]; (b) S protein of SARS-CoV-2 can interact with the heparin-binding proteins tau and TDP-43, which may give rise to the aggregation of tau and TDP-43 and, subsequently, the development of FTD, ALS, and AD. TDP-43, TAR DNA-binding protein 43; ALS, Amyotrophic lateral sclerosis [110, 170]; (c) The vicious cycle which induces PD. TLR4 signaling pathway initiating innate immune response can be elevated by SARS-CoV-2, which is a potential factor capable of inducing αS misfolding and aggregation resulting in dopaminergic neuronal damage. Afterward, αS can be released extracellularly and potentiates immune responses in a TLR4-dependent manner. Also, αS aggregation can be accelerated via direct interaction with SARS-CoV-2 N-protein; PD, Parkinson's disease; TLR4, Toll-like receptor; αS, alpha-synuclein [192, 194, 196, 199]
Citation: Physiology International 109, 2; 10.1556/2060.2022.00019
Vascular dementia
Vascular cognitive impairment (VCI) is a heterogeneous group of disorders due to vascular etiology, with varying severity of cognitive deficits. In this regard, vascular dementia (VaD), which is considered as a major VCI, is the most severe form of VCI [119]. VaD is the second most common subtype of dementia after AD, estimated to represent 20% of dementia cases in North America and Europe (112–114). According to VCCCS (Vascular Impairment of Cognition Classification Consensus Study) conceptualization, VaD is made up of different main subtypes comprising post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct (cortical) dementia, and mixed dementias (combination between vascular and neurodegenerative diseases) [120], which result from small-, large-, and mixed- small/large vessel diseases [121].
Small vessel disease (SVD) consists of different pathological findings such as small infarcts, microscopic infarcts, microbleeds, arteriolosclerosis, intracranial atherosclerosis, and cerebral amyloid angiopathy [119]. According to various studies, SVD is the most common cerebrovascular pathology found in examined samples of VaD patients [122–124]. In this respect, it is noticeable that SVD is associated with factors such as age, diabetes mellitus, hypertension and stroke, [125]and the key pathophysiological mechanisms underlying SVD are linked to ischemia, inflammation, and oxidative stress [124, 126]. It has been demonstrated that following ischemia and inflammation, endothelial activation takes place. Endothelial activation, which is deemed as the overexpression of adhesion molecules such as VCAM-1, ICAM-I, P-selectin and E-selectin, is linked to endothelial dysfunction [126, 127]. The effect of vascular inflammation and endothelial dysfunction on the structural and functional cerebrovascular alterations in SVD is documented [128, 129]. On this line, renin-angiotensin–aldosterone system (RAAS) activation is shown to have a role in provoking oxidative stress, small cerebral-vessel inflammation, endothelial dysfunction, and subsequent increased BBB permeability via the influence of angiotensin II (Ang II) [126, 130, 131]. In this respect, the effect of aldosterone on promoting cerebrovascular inflammation and endothelial dysfunction is also demonstrated [132].
In another respect, it is noteworthy to mention that one of the other subtypes of VaD, namely Post-stroke Dementia results from stroke. In this way, dementia can develop in 10% of patients after the first stroke and in a third of patients following recurrent stroke [124]. Stroke is the second leading cause of death; it is a medical condition in which significant complications such as cell death are caused by poor blood flow to the brain. There are two main types of stroke: ischemic, due to interruption of blood flow, and hemorrhagic, which is caused by bleeding [133]. In this view, it has been shown that dementia may develop following each of them [124]. The key events contributing to stroke pathology are inflammation, rapid reduction of ATP, loss of homeostasis, acidosis, increased intracellular calcium levels, excitotoxicity, free radical-mediated toxicity, cytokine-mediated cytotoxicity, impairment of the BBB, activation of glial cells, and infiltration of leukocytes [134–141].
The possible link between SARS-CoV-2 infection and the development of VaD
According to several lines of studies, it is suggested that COVID-19 infection may drive the onset of hypertension through increasing the signaling of Ang II, which is one of the key effectors in RAAS [142, 143]. SARS-CoV-2 causes the downregulation of ACE2 [144]; subsequently, it would lead to the accumulation of Ang II [145]. Ang II, in turn, through its effect on the angiotensin 1 receptor, enhances aldosterone production. Ang II in concert with aldosterone can also exert pro-inflammatory effects by the mediation of angiotensin 1 receptor and mineralocorticoid receptor, respectively, which can result in cerebrovascular inflammation and endothelial dysfunction [132]. Accordingly, recent compelling evidence suggests that the pro-inflammatory action of Ang II and aldosterone can flare up under the influence of SARS-CoV-2 [146]. As mentioned above, several studies have shown that SVD is the most common cerebrovascular pathology found in VaD [124]. In addition, the role of vascular inflammation and endothelial dysfunction in SVD is documented [128, 129]. In this relevance, several studies have demonstrated the association of Ang II and aldosterone with cerebral SVD [147, 148]. This association is reasonable considering the pro-inflammatory action of Ang II and aldosterone, which can result in cerebrovascular inflammation and endothelial dysfunction. Taking into account the enhancing effect of SARS-CoV-2 on the pro-inflammatory action of Ang II and aldosterone [146], and the positive association of Ang IIa and aldosterone with SVD [147, 148], it is proposed that SARS-CoV-2 may have a role in the development of SVD and VaD. On the other hand, it has been stated above that hypertension is one of the risk factors for SVD and VaD [124, 125]. In this respect, if the control of high blood pressure becomes poor, the alterations related to hypertension, such as small vascular lesions and inflammatory reactions, will take place gradually in small cerebral vessels [149]. Considering the above-mentioned fact that SARS-CoV-2 may cause hypertension and according to the presumed effect of hypertension on SVD progression, the possible role of SARS-CoV-2 infection in the development of hypertension and subsequent SVD and VaD would be highlighted.
In another respect, it has been reported that the risk of ischemic stroke during COVID-19 is roughly 5%, but COVID-19-related hemorrhagic strokes are far less common than ischemic strokes [150]. In this view, it has been shown that SARS-CoV-2 infection affects the initiation of stroke and the intensification of stroke as a preexisting neurological disorder [151, 152]. This is a noticeable subject that is caused by cytokine storm, hypoxia-induced ischemia secondary to severe pulmonary disease, thrombotic microangiopathy, endotheliopathy, and coagulation [153]. Thus, SARS-CoV-2 infection has a role in progressing stroke; clinically, this has also been reported in several cases of COVID-19 presenting stroke symptoms [34, 154–160].
As mentioned earlier, studies have documented that stroke can be a significant factor for biochemical dysfunction in the brain, ultimately leading to VaD [124]. By considering the role of SARS-CoV-2 infection in the progression of stroke, as well as the association of stroke with VaD, this virus may also have a role in developing post-stroke dementia. These matters need to be evaluated clinically in the future.
Frontotemporal disorder
Frontotemporal disorder (FTD), and its pathological presentation, namely Frontotemporal Lobar Degeneration, encompasses several types of dementia involving the frontal and temporal lobes [161, 162]. FTD was first described by Pick in 1892 (Neary et al., 2005). FTD is presented as behavioral or language disorders, including significant social and personal behavior changes, apathy, blunting of emotions, deficits in both expressive and receptive language, and frontal and temporal lobe atrophy [163–165]. It has been shown that FTD's pathology is associated with three main proteins, namely the fused in sarcoma protein (FUS) in FTLD-FUS, the microtubule-associated protein Tau in FTLD-Tau [114], and TAR DNA-binding protein 43 (TDP- 43) in FTLD-TDP, which are sufficient to cause these types of NDs [166, 167]. In this regard, these proteins in CNS can induce widespread neurotoxicity and cell death due to the accumulation of misfolded tau, FUS, and TDP-43 intracellular inclusions [162, 168, 169].
The possible link between SARS-CoV-2 infection and the development of FTD
It has been reported that SARS-CoV-2 exposure is associated with altered distribution of tau protein from axons to soma and aberrant tau phosphorylation (hyperphosphorylation), which lead to neurodegeneration and apparent neuronal death [110]. In this view, to have more explanation, tau phosphorylation is induced by the activation of several kinases, whose activation is inhibited by ACE2-related pathways. However, the process of inhibiting these signaling pathways can be caused by the COVID-19 virus resulting in tau phosphorylation [113, 115] (shown in Fig. 2). Also, the SARS-CoV-2 S protein can interact with the heparin-binding site. In this site, there are several heparin-binding proteins such as tau and TDP-43, which are aggregation-prone. Viruses enter the cell via HSPG-mediated endocytosis and use the endosomal pathway to travel through the cytoplasm and reach the nucleus to initiate their replication and infection. On this line, there is a possibility that due to the interaction between SARS-CoV-2 S protein and the proteins tau and TDP-43, the aggregation of the proteins mentioned will be increased; this eventually can lead to the development of NDs such as FTD. Thus, this binding can induce aggregation of these proteins, which leads to NDs such as FTD [170, 171] (shown in Fig. 2). Since aggregation of tau and TDP-43 are considered pathophysiological mechanisms underlying FTD, it can be suggested that SARS-CoV-2 infection may have a role in developing FTD. This possible effect of SARS-CoV-2 remains to be evaluated in the future.
Parkinson's disease (PD)
PD is a long-term degenerative disease of the central nervous system that mainly involves the motor system, increasing with age, such as those above 60 years [172, 173]. The prodromal features usually emerge slowly, and as the disease worsens, the non-motor symptoms become more common. In this regard, hyposmia is one of the most common non-motor symptoms in PD [174]. The core symptoms of PD are tremor, rigidity, slowness of movement, and difficulty with walking [175]; these motor presentations mainly result from the death of cells in the substantia nigra (SN), leading to midbrain dopaminergic neuron deficit [176]. Also, cognitive and behavioral problems occur with depression, anxiety, and apathy detected in people with PD [177]. The neuropathological hallmarks of PD include progressive dopaminergic neuronal cell loss in the SN and other brain regions such as the locus ceruleus, as well as abnormal accumulation of the protein alpha-synuclein (αS) in the form of Lewy bodies and Lewy neurites which is induced by misfolding of αS [178].
The possible link between SARS-CoV-2 infection and the development of PD
The initiation of PD symptoms that were previously reported in 8 cases of COVID-19 [179–185] supports the possible influence of SARS-CoV-2 infection on the development of PD. Also, there is some evidence that SARS-CoV-2 infection has a possible role in inducing and progressing PD, summarized in this section. The ability of coronaviruses to enter the CNS through the nasal cavity with subsequent neuronal death has been shown in animal studies [186, 187]. As reported, hyposmia has been induced in COVID-19 patients without nasal obstruction and rhinorrhea, which is a common prodromal feature of PD [188–191]. Moreover, as mentioned earlier, SARS-CoV-2 can induce inflammation, which may damage dopaminergic neurons through αS modification [192]. In this regard, Toll-like receptors (TLRs) such as TLR4 (a signaling receptor in innate immunity that is a specific immunologic response to infection), which possesses a strong binding affinity to SARS-CoV-2 S protein [193], can be elevated by the SARS-CoV-2-induced inflammatory process, induce proinflammatory cytokines through the TLR4 signaling pathway in microglia [194]. The resulting inflammation is a potential factor capable of inducing αS misfolding, and aggregation in neurons can give rise to neuronal damage [195]. As a vicious cycle, different forms of αS can be released extracellularly from the damaged neurons activating TLR4 and leading to further inflammatory signals in the neural network [194] (shown in Fig. 2). This process spreads from cell to cell and hampers the brain, since αS toxicity has a role in cellular dysfunction such as mitochondrial abnormalities, axonal transport deficits, and synaptic transmission alterations [62, 194, 196–200]. Also, recently, direct interaction between the nucleocapsid protein (N-protein) of SARS-CoV-2 and αS has been documented in a way that SARS-CoV-2 N-protein speeds up the αS aggregation process [199] (shown in Fig. 2). In addition, it has been shown that lesions on basal ganglia may occur through thromboembolic encephalopathy and cytokines induced by SARS-CoV-2 infection [201–204]. By taking into consideration the SN, which is a midbrain dopaminergic nucleus, and its critical role in modulating motor movement as a part of the basal ganglia circuitry, and the lesion-inducing effect of SARS-CoV-2 on basal ganglia, it can be assumed that dopaminergic neurons may be damaged via this virus leading to motor disturbances.
Further, there is a possible influence of SARS-CoV-2 infection on the development of PD via accumulation of angiotensin II. In this view, in a study on the regulatory role of angiotensin II in the synthesis of the enzymes involved in catecholamine biosynthesis such as DA has been documented [205]. In another study, the ACE2 receptor has been detected in the mitochondria isolated from cell cultures derived from dopaminergic neurons [206]. Also, it is assumed that SARS-CoV-2 can cause downregulation of ACE2 [144], which can lead to the accumulation of angiotensin II [145], resulting in DA metabolic dysfunction [207]. Thus, the mentioned data illustrate that SARS-CoV-2 through ACE2 located on dopaminergic neurons and accumulation of angiotensin II may promote the development of PD in COVID-19 patients.
According to significant observational literature discussed above, since protein misfolding and aggregation along with DA deficit are a set of pathophysiological mechanisms in PD, and considering the inducing effect of SARS-CoV-2 infection on protein misfolding and aggregation and oxidative stress in dopaminergic neurons [192], it can be suggested that SARS-CoV-2 infection may also have a role in triggering PD. On this line, as mentioned above, the initiation of PD manifestations in 8 cases of COVID-19 [179–185] upholds the feasible influence of SARS- CoV-2 infection on the development of PD; however, the long-term observation of persons with a past medical history of COVID-19 along with conducting research experiments will assess the validity of this assumption in the future (Table 1). In another aspect, a cohort study has demonstrated a significant worsening of motor and nonmotor symptoms in PD patients during the COVID-19 illness [208]. This, in turn, postulates the possible role of SARS-CoV-2 infection in the exacerbation of neurological symptoms in PD patients.
COVID-19 related cases of parkinsonism
| Case I | Case II | Case III | Case IV | |
| Age & Gender | 35-year-old female | 45-year-old male | 58-year-old Male | 64-year-old Female |
| Clinical presentations of COVID-19 | Fever, cough, sneezing, rhinorrhea, diarrhea, myalgia, anosmia, hypogeusia | Fatigue, shortness of breath, chest pain without fever, and loss of smell | Dry cough, fever, nausea, and shortness of breath | Fever, fatigue, and loss of smell |
| COVID-19 severity | Mild | Moderate requiring hospitalization | Severe with desaturation requiring ICU admission | Mild |
| COVID-19 to PD features interval | 10 days | 2–3 weeks | 32 days | 5 days |
| Core features of PD | Right side rigidity, bradykinesia | Tremor, bradykinesia, rigidity in right side more than left side | Right side–dominant hypokinetic-rigid syndrome with rest and postural tremor | Left side bradykinesia rigidity and rest tremor |
| Nonmotor symptoms of PD | Hypophonia, hypomimia, gait impairment, and slow saccades | None | None | Hypomimia |
| Prodromal PD symptoms | None | None | None | Constipation |
| Underlying medical conditions | None | Hypertension | Hypertension and dyslipidemia | ND |
| Family history of PD | None | ND | None | None |
| Brain imaging | Reduced The function of the nigrostriatal dopamine system, akin to PD |
Reduced function of the nigrostriatal dopamine system, akin to PD | Reduced function of the nigrostriatal dopamine system, akin to PD | Reduced right putamen uptake |
| Genetic testing for familial PD | ND | Negative | ND | ND |
| Drug treatment | Levodopa/benserazide | Pramipexole | Spontaneously | ND |
| Reference |
(Faber et al., 2020) [180] |
(Cohen et al., 2020) [181] |
(Méndez-Guerrero et al., 2020) [182] |
(Makhoul and Jankovic, 2021) [183] |
| Case V | Case VI | Case VII | Case VIII | |
| Age & Gender | 35-year-old female | 72-year-old male | 66 -year-old male | 74 -year-old male |
| Clinical presentations of COVID-19 | Fever, Hyposmia, encephalitis | Fever, chills, cough, and breathlessness | Cough, hoarseness of voice, and one episode of a generalized tonic-clonic seizure | ND |
| COVID-19 severity | ND | ND | ND | ND |
| COVID-19 to PD features interval | ND | 5 days | One week | 8 weeks |
| Core features of PD | Tremor, cogwheel rigidity, bradykinesia, & postural instability | Cogwheel rigidity, postural instability, and bradykinesia | Rigidity in his right upper and lower limbs with severe bradykinesia | rigidity, postural instability, and motor slowing |
| Nonmotor symptoms of PD | Hypomimia | Loss of smell, | None | ND |
| Prodromal PD symptoms | None | ND | ND | ND |
| Underlying medical conditions | ND | Orthostatic hypotension | ND | ND |
| Family history of PD | ND | ND | ND | ND |
| Brain imaging | Bi pallidal lesion | ND | Gliosis in bilateral temporal lobes, periventricular punctate white matter ischemic changes in bilateral frontal and parietal lobes and age- related cerebral and cerebellar atrophy. | Ischemic changes in periventricular white matter |
| Genetic testing for familial PD | ND | ND | ND | ND |
| Drug treatment | Levodopa/carbidopa | ND | Levodopa-carbidopa | Levodopa- carbidopa |
| Reference | (Ayele et al., 2021) [185] | (Rao et al., 2022) [184] | (Rao et al., 2022) [184] | (Rao et al., 2022) [184] |
ND: not determined.
Amyotrophic lateral sclerosis (ALS)
ALS is an inevitably fatal neurological disorder that affects the upper and lower motor neurons in the motor cortex, the brain stem nuclei, and the anterior horn of the spinal cord leading to progressive muscle weakness and wasting, which affect chewing, swallowing, speaking, breathing, and cause tongue atrophy and fasciculations, which compromise the autonomy of the subject in daily life [209–212]. It has been documented that genetic causes involved in ALS are hexanucleotide expansions in chromosome 9 open reading frame 72 and mutations in superoxide dismutase 1 (SOD1), TDP-43, FUS, and TANK-binding kinase 1. Also, in both sporadic and familial ALS patients, there are cytoplasmic aggregations of TDP-43 and SOD1, which show a significant extent of neuronal damage resulting from aggregates of these proteins in various tissues that share a distinctive b-sheet-rich fibrillar ultrastructure leading to cell death [213–218].
The possible link between SARS-CoV-2 infection and the development of ALS
There is several evidence available that shows SARS-CoV-2 infection has a possible role in developing ALS. In this respect, it has been reported that the health status of ALS patients during the COVID-19 illness worsened, showing the impact of SARS-CoV-2 infection on these patients [219]. Also, ACE2 may be expressed in the motor cortex, in the cytoplasm of neurons, which represent cerebral regions involved in the pathogenesis of ALS [220]. Further, it can be proposed that SARS-CoV-2 has a possible role in ALS underlying pathophysiology such as TDP-43 aggregations [170]. In this view, based on the effect of SARS-CoV-2 on protein misfolding resulting from SARS-CoV-2-induced oxidative stress, this virus may aggregate TDP-43 in the brain, which can be considered the crucial reason behind ALS [170] (shown in Fig. 2). Also, as mentioned earlier, binding of the SARS-CoV-2 S protein to heparin-binding proteins can induce aggregation of TDP-43, leading to neuron damage. There have not yet been any reports of cases of ALS in patients following COVID-19. However, based on the effect of SARS-CoV-2 on the aggregation of TDP-43, which is considered part of the pathophysiological mechanism underlying ALS, it can be suggested that SARS-CoV-2 infection may have a role in developing ALS.
Conclusion
As mentioned above, COVID-19 is a contagious disease caused by SARS-CoV-2. SARS-CoV-2 gets into contact with cells and binds to its receptors that assist in its entry into cells, including brain cells. This virus can infect the brain and the nervous system, presenting nervous system symptoms in COVID-19 patients. The COVID-19 patients may present various neurological disorders such as dementia, one of the most devastating diseases [221].
Interestingly, several cases presenting parkinsonian features, five days to 8 weeks after initial COVID-19 symptoms, have been recently reported [183], which raises the possibility of NDs development following COVID-19 infection. In this review, we culled the documentation in which the inducing effect of SARS-CoV-2 on ER stress and prolonged UPR may have a role in the progression of NDs due to activation of the pathways of apoptosis, autophagia and inflammation. In continuation, the inducing effect of SARS-CoV-2 on the progression of pathophysiological mechanisms that are exclusive for the well-known NDs such as VaD, AD, PD, FTD, and ALS was explained.
The molecular pathways stated here are not the only mechanisms that can flare up the clinical presentations of the NDs under the effect of SARS-CoV-2. In another aspect of view, it has to be mentioned that during the COVID-19 pandemic, noticeable psychological disturbances such as anxiety have been detected in patients with NDs. Pertinently, the reason is more ascribed to the factors such as changes in daily life, the imposition of quarantine measures, the fear of becoming infected with the virus SARS-CoV-2, and worrying about drug availability [222, 223]. Several analytical studies have displayed the association of anxiety with a rise in the risk of all-cause dementia [224]. This critical topic highlights that the exacerbation of the NDs can also be affected by the COVID-19 pandemic-related psychological status.
According to the possible mechanisms that highlight the impact of SARS-CoV-2 infection on the initiation of NDs, nowadays, there is an underdebated line of thought maintaining that the COVID-19 pandemic might be associated with the boost in the epidemic of NDs [225]. In this regard, viral infection has been identified only as one of the potential risk factors for NDs and other risk factors such as genetic. Therefore, it is not clear whether or not we will face a coming epidemic of NDs, and this is a topic that needs to be elucidated in the future. In other views, based on the before-mentioned molecular pathways showing a possible role for SARS-CoV-2 infection in developing the NDs, SARS-CoV-2 infection is not only capable of intensifying the clinical presentations of patients with NDs but may also shift the time of disease onset to an earlier age. This is another subject that remains to be clarified clinically in the future.
Conflict of interest
The authors declare that they have no conflict of interest with the contents of this article.
Author contributions
All authors have agreed to be named as authors of this manuscript. Any work (literature review, text, or theories) of others besides the authors has been properly acknowledged. The work is original and not previously published.
Funding sources
No financial support was received for this study.
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