- 1Laboratório de Investigações em Neurodegeneração e Infecção, Hospital Universitário João de Barros Barreto, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Brazil
- 2Laboratório de Microscopia Eletrônica, Instituto Evandro Chagas, Belém, Brazil
- 3Seção de Arbovirologia e Febres Hemorrágicas, Instituto Evandro Chagas, Ananindeua, Brazil
- 4Department of Pharmacology, University of Oxford, Oxford, United Kingdom
- 5Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- 6Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
The COVID-19 pandemic imposed a series of behavioral changes that resulted in increased social isolation and a more sedentary life for many across all age groups, but, above all, for the elderly population who are the most vulnerable to infections and chronic neurodegenerative diseases. Systemic inflammatory responses are known to accelerate neurodegenerative disease progression, which leads to permanent damage, loss of brain function, and the loss of autonomy for many aged people. During the COVID-19 pandemic, a spectrum of inflammatory responses was generated in affected individuals, and it is expected that the elderly patients with chronic neurodegenerative diseases who survived SARSCoV-2 infection, it will be found, sooner or later, that there is a worsening of their neurodegenerative conditions. Using mouse prion disease as a model for chronic neurodegeneration, we review the effects of social isolation, sedentary living, and viral infection on the disease progression with a focus on sickness behavior and on the responses of microglia and astrocytes. Focusing on aging, we discuss the cellular and molecular mechanisms related to immunosenescence in chronic neurodegenerative diseases and how infections may accelerate their progression.
Introduction
The ongoing viral pandemic has imposed behavioral changes resulting in increased social isolation and a more sedentary life, which has affected all age groups (Schwabenland et al., 2021; Yang et al., 2021). However, social isolation during the COVID-19 pandemic especially affected the elderly population with comorbidities, who were already exhibiting mild or moderate cognitive deficits and senile cognitive decline associated with neurodegenerative diseases (Tangalos and Petersen, 2018; Juan and Adlard, 2019; Noguchi et al., 2021).
Older adults are more vulnerable to infectious diseases (Clark et al., 2020; Cunha et al., 2020) due to immune system dysregulation (Müller et al., 2019), together with cellular and signaling pathway impairments, which contribute to cell cycle arrest (Calcinotto et al., 2019), oxidative stress (Liguori et al., 2018), mitochondrial dynamic abnormalities (Kudryavtseva et al., 2016), autophagic disruption (Wong et al., 2020), immunosenescence (Fülöp et al., 2016; Pawelec, 2018), and neuroinflammation (Ransohoff, 2016). Dysregulation of these processes is known to be associated with the pathogenesis of neurodegenerative diseases (Brites, 2015; Schmeer et al., 2019; Wissler Gerdes et al., 2020). During the COVID-19 pandemic, these vulnerabilities have led to an increase in mortality rate that reached 1.4–15% in people in the age group between 65 and 85 years old, as compared with a much lower rate of 0.01–0.4% in the age group from 25 to 55 years (Levin et al., 2020). A meta-analysis of the infection-fatality rate has been estimated to be 0.53–0.82% (Meyerowitz-Katz and Merone, 2020). For those responsible for implementing the COVID-19 health policy, it is now clear that COVID-19 pathology extends well beyond lung pathology (Pannone et al., 2021) as is there now evidence of kidney damage (Gabarre et al., 2020; Hassanein et al., 2020; Ronco et al., 2020), pathological sequelae in the hepatobiliary, gastrointestinal, pancreatic (Jothimani et al., 2020; Lee et al., 2020; Patel et al., 2020), reproductive (He et al., 2021), cardiovascular (Bansal, 2020; Spuntarelli et al., 2020), and central nervous (Fiani et al., 2020; Nagu et al., 2021) systems. As a consequence, the potential for the interaction between the activated systemic immune system and neurodegenerative disease pathology is increased, and the mechanisms are likely to be more complex than previously envisaged.
The decline in physical activity imposed by restriction of outdoor activities and sedentary behaviors (Stockwell et al., 2021) is known to exacerbate chronic illnesses directly and has led to an increase in stress, anxiety, and depression that is also known to have an impact on comorbidities. For example, studies have highlighted that cardiovascular and cerebrovascular dysfunctions or kidney damage (Lee A. C. et al., 2021), metabolic disorders (Kullmann et al., 2016; Dye et al., 2017; Li et al., 2017; Bailly et al., 2021), motor impairments, and other chronic illnesses are aggravated by an increased sedentary life (Araújo et al., 2021; Awogbindin et al., 2021; de Boer et al., 2021; Engels et al., 2021; Salman et al., 2021), and thus these individuals are likely to require more medical attention and continued monitoring for potential long-term sequelae.
It is already known that SARS-CoV-2 binds to the receptor for angiotensin-converting enzyme 2 (ACE2) (Hoffmann et al., 2020; Zhang et al., 2020; Zhou et al., 2020), which is most prominently expressed by epithelial and endothelial cells, and, to a lesser extent, by neurons and glial cells (McQuaid et al., 2021; von Bohlen Und Halbach, 2021). The presence of SARS-CoV-2 in droplets in the air enters the upper respiratory tract, infecting the nasal and pharyngeal epithelia and the bronchial and alveolar epithelium (Bourgonje et al., 2020). In symptomatic patients, nasal swabs have shown higher viral loads than throat swabs (Zhou et al., 2020) owing to the high expression of ACE2 in the nasal epithelial cells (Sungnak et al., 2020). The viral protein Spike interacts with the ACE2 receptor in several different tissues, such as the central nervous system, where it increases angiotensin II and activates nicotinamide dinucleotide phosphate oxidase2 (NOX2) enzyme with the subsequent release of reactive oxygen species (ROS) and inflammatory mediators (Sindona et al., 2021).
Patients with SARS-CoV-2 show elevated levels of pro-inflammatory cytokines mediated by the dysregulation of the nuclear factor kappa B (NF-κB) signaling pathway (Hammoudeh et al., 2021; Su et al., 2021) and downstream enhanced expression of pro-inflammatory genes that translate into increased neuroinflammation (Liu et al., 2017). Although, some reports have addressed the potential long-term effects of chronic mild neuroinflammation in neurodegenerative diseases and the acceleration of progression rate (Alonso-Lana et al., 2020; Dewanjee et al., 2021), the persistence of neuroinflammatory events induced by SARS-CoV-2 on a background of neuropsychiatric and neurological sequelae (Carod-Artal, 2020; Dinakaran et al., 2020; Troyer et al., 2020; Wang et al., 2020; Yachou et al., 2020; Swain et al., 2021) have the potential to aggravate the pathophysiological aspects in the survivors (Perry, 2010; Holmes et al., 2011; Amor et al., 2014; Alam et al., 2017; Idrees and Kumar, 2021; Marques Zilli et al., 2021; Too et al., 2021).
Thus, we considered it to be of interest to review the potential consequences of the effects of the COVID-related inflammatory response on the immune responses linked to chronic neurodegeneration, associated with central or peripheral virus infections. To that end, we here revisited the influences of social isolation, sedentary life, and central or peripheral infections on mouse prion disease progression, as a proxy for the exacerbated immune response of prion-like chronic neurodegenerative diseases (Fernández-Borges et al., 2015; Armstrong, 2020; Goedert, 2020; Hosseini et al., 2021) under similar conditions.
Experimental Mouse Prion Disease and Prion-Like Chronic Neurodegenerative Diseases
From a neuropathological point of view, several parallels have been established between prion diseases (Orge et al., 2021), Alzheimer’s disease (AD), and other prion-like neurodegenerative disorders (Ransohoff and Perry, 2009; Alpaugh and Cicchetti, 2021; Annadurai et al., 2021; Contiliani et al., 2021; Ritchie and Barria, 2021). Although transmissibility remains a unique characteristic of prion diseases, protein misfolding disorders share protein aggregation as a common mechanism as the disease spreads from cell to cell (Diack et al., 2016; Scheckel and Aguzzi, 2018).
Alzheimer’s and Prion’s pathologies share synaptic dysfunctions and axonal trafficking defects (Senatore et al., 2013; Zamponi et al., 2017; Soto and Pritzkow, 2018; Song et al., 2021) and similar alterations in the processing of neuronal membrane proteins, together with insoluble deposits of amyloid-β (Aβ) peptide and amyloid plaques. Because of the predictable course of the pathology along with anatomical locations (Braak and Braak, 1991; Scott et al., 1992; DeArmond, 1993; Eikelenboom et al., 1994, 2002; Zamponi and Pigino, 2019), prion disease in the murine model has been proposed as an important tool for experimental studies searching for mechanisms underlying chronic neurodegeneration (Betmouni et al., 1996; Diack et al., 2016).
Prions are proteinaceous infectious pathogens, devoid of functional nucleic acids that cause a group of fatal neurodegenerative diseases by self-propagating misfolding protein deposition and an associated inflammatory response (Carlson and Prusiner, 2021; Orge et al., 2021). Also known as transmissible spongiform encephalopathies, they can produce diseases in several species of mammals, such as Creutzfeldt-Jacob Disease in humans, scrapie in sheep, and bovine spongiform encephalopathy (Prusiner, 1996; Ayers et al., 2020). Prion agents are composed exclusively of a modified form of normal cellular prion protein (PrPC), which is then converted into an insoluble form resistant to the action of proteases (PrPSc) (Bolton et al., 1982; Prusiner, 1982; Carroll and Chesebro, 2019). This altered protein is deposited in the parenchyma of the central nervous system where it induces a chronic neuroinflammatory response (Betmouni et al., 1996; Carroll and Chesebro, 2019). Immunohistochemical studies have shown that PrP is the main component of the Aβ plaques in mammalian prion diseases (DeArmond et al., 1985; Priola, 2017). The experimental prototypic murine model of prion disease is well established and is generated by injecting the prion agent ME7 into the hippocampus of the inbred C57BL/6J mouse strain (Betmouni et al., 1996). Distinct mouse strains may show diverse incubation periods and end-stage neuropathological features (Borner et al., 2011). However, similar early synaptic loss precedes neuronal degeneration and associates with early behavioral deficits in distinct prion disease strains (Bruce et al., 1991; Cunningham et al., 2005a; Borner et al., 2011; Hilton et al., 2013). An extended incubation period, together with astrocyte and microglia activation, neuronal death, and neuropil vacuolization are typical neuropathological features of the mouse prion disease models (Williams et al., 1994; Betmouni et al., 1996). While tau phosphorylation changes are limited to the end-stage prion pathology (Asuni et al., 2010), induction of type I interferons (IFN-I) results in significant phenotypic alterations in microglia that accelerates disease progression (Nazmi et al., 2019). Neuronal loss develops late in the disease and occurs topographically through neuroanatomical pathways that vary according to the prion agent ‘strain’ and the animal model that is used (Fraser et al., 1989; Jeffrey et al., 2000; Reis et al., 2015). Heparan sulfate proteoglycan is associated with Aβ plaques (McBride et al., 1998), and neuronal loss seems to be associated with oxidative stress (Brown, 2005; Bettinger and Ghaemmaghami, 2020) and apoptotic mechanisms via the proteolytic activation of the protein kinase Cδ (Harischandra et al., 2014).
The mechanisms underlying prion-induced neurodegeneration have been widely investigated (Hughes and Halliday, 2017). Most of these studies point to the fact that the PrPC protein has important roles as an antioxidant molecule and an apoptotic regulator, and that its depletion in the course of the disease can induce direct neurotoxic effects by oxidative stress (Collinge, 2001; Shah et al., 2018). Recently, it has been demonstrated that chronic neuroinflammation, shared by many neurodegenerative disorders (Amor et al., 2014; Obst et al., 2017), is generated through the dysregulation of the NLRP3 inflammasome, a central component of the innate immune system that induces pro-inflammatory cytokine production and cell death (Coll et al., 2016; Holbrook et al., 2021).
Social Isolation and Behavioral Changes in Chronic Neurodegenerative Diseases
The forced and prolonged social isolation caused by the COVID-19 pandemic has aggravated the psychiatric symptoms of older people with cognitive impairments (Barguilla et al., 2020; Manca et al., 2020). In fact, demented patients worsened in their cognitive, behavioral, and psychological symptoms, and the mortality rate associated with SARS-Cov-2 infection among these patients is very high (Toniolo et al., 2021b). The detrimental effects of social isolation on human health and cognition have been highlighted previously (House, 2001; Friedler et al., 2015). Despite these warning signs, there is a huge growth in the number of people who still live alone (Snell, 2017).
Evidence from both animal models and humans demonstrated the physiological benefits of social interaction (Krueger et al., 2009; Andrew and Rockwood, 2010; Karelina and DeVries, 2011; Holt-Lunstad, 2018). Therefore, detrimental effects of social isolation have been recognized systematically as a source of chronic stress associated with the increased prevalence of vascular and neurological diseases (Friedler et al., 2015). In addition, it has been suggested that reduction of social engagement between midlife and late-life periods can be predictive of functional disabilities (Guo et al., 2020), cognitive decline (Huang et al., 2020), and dementia and mortality (House et al., 1988; Saczynski et al., 2006; Daffner, 2010; Krivanek et al., 2021). Social isolation also increases the risk of chronic neurodegenerative diseases (Heneka and O’Banion, 2007; Amieva et al., 2010; Heneka et al., 2010; Lyman et al., 2013; Hajek et al., 2021) with differential neuro-immune markers for social engagement and loneliness (Walker et al., 2019). Previous findings in a mouse model of prion disease identified early behavioral and neuropathological changes associated with the inbred (C57Bl6J), as compared to the outbred (albino Swiss mouse) model of prion disease (Cunningham et al., 2005a; Borner et al., 2011). Nevertheless, little is known about the influence of social isolation on the progression of such diseases.
Previous studies using environmental manipulations in the triple transgenic mouse model of AD (3xTg-AD) were effective in modifying several behaviors but did not change genetically determined AD-like symptoms (Pietropaolo et al., 2009).
Sedentary Life and Chronic Neurodegenerative Diseases
Environmental enrichment (EE) and physical exercise have been used to mimic an active lifestyle in humans and previous findings demonstrated that an active life slows AD progression (Silveira et al., 2018; de Freitas et al., 2020) and Huntington’s disease progression (van Dellen et al., 2000; Hockly et al., 2002; Spires et al., 2004), and extends the disease time course in experimental models. These animal models include the transgenic mice co-expressing familial AD-linked mutations on the amyloid precursor protein (APP) and presenilin 1 (PS1) (Lazarov et al., 2005), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) Parkinson’s disease model (Faherty et al., 2005; Jadavji et al., 2006), and the mice expressing the human SOD1(G93A) gene mutation, the most common model of amyotrophic lateral sclerosis (Stam et al., 2008) and in the mouse prion disease (Bento-Torres et al., 2017).
Because EE and exercise moderate immune responses (Burtscher et al., 2021; Chastin et al., 2021; do Brito Valente et al., 2021; Filgueira et al., 2021; Proschinger et al., 2021; Sellami et al., 2021), and aging dysregulates immune responses (Brites, 2015; López-Ortiz et al., 2021; Martinez et al., 2021; Mathot et al., 2021), we previously hypothesized that EE and aging would, respectively, delay and accelerate prion disease progression (Bento-Torres et al., 2017). However, we found that after intracerebral injection of the ME7 agent into the dorsal striatum, aged mice exhibited significantly reduced disease progression when compared to young mice injected with ME7 (Bento-Torres et al., 2017).
To illustrate the effects of exercise and EE on disease progression after intraperitoneal injection, we selected two hippocampal-dependent tasks: burrowing (Deacon et al., 2001; Deacon, 2009) and the Morris water maze (Morris et al., 1982; Morris, 1984). Burrowing behavior was found to be the most sensitive task to detect early hippocampal dysfunction in mouse prion disease, which coincided with the onset stage (Deacon et al., 2001; Cunningham, 2005). Similarly, the Morris water maze task in rat AD models was found to detect subtle impairments in aged mice (Sun et al., 2019).
A systematic review dedicated to the identification of the beneficial effects of physical exercise in AD suggests that aerobic exercises are an effective intervention that can attenuate the neuropsychiatric symptoms as the disease progresses (Mendonça et al., 2021). Evidence also indicates that physical exercise leads to the release of-induced myokines, a group of peptides produced and secreted by skeletal muscles during exercise (Pedersen, 2009), which have been shown to haveneuroprotective roles (Petersen and Pedersen, 2005; Astrom et al., 2010; de Freitas et al., 2020; Lee B. et al., 2021). Similarly, EE seems to prevent microglia-mediated neuroinflammation (Almutairi et al., 2016).
Exacerbated Inflammatory Response and Sedentary Lifestyle
Chronically activated neuroinflammatory processes in neurodegenerative diseases play a central role in their pathogenesis (Heneka et al., 2015; Ransohoff, 2016). Because microglial proliferation is a major component in the progression of chronic neurodegeneration (Gómez-Nicola et al., 2013; Subhramanyam et al., 2019; Azam et al., 2021) and the microglial innate immune response in prion disease (Peggion et al., 2020) is also considered to contribute to the activation of the peripheral immune system at draining lymph nodes and the spleen (Vincenti et al., 2015), it is thought that interactions with other immune cell populations may accelerate the spread of neurodegeneration in prion disease brain (Mabbott et al., 2020). Indeed, splenectomy before intraperitoneal prion infection was shown to extend survival times but had no effect on disease pathogenesis when intracerebral injections of prions were performed (Fraser and Dickinson, 1970; Mabbott et al., 2020). Following peripheral exposure, many prions replicate in the lymphoid tissues before entering the central nervous system, and prion pathogenesis is impaired dramatically in aged mice when compared with young animals (Brown and Mabbott, 2014). Thus, owing to the compromised immunosenescence microglial response in aged mice (Brites, 2015; Carvalho-Paulo et al., 2021), a stronger inflammatory response would be expected in young mice (Bento-Torres et al., 2017).
Previous findings in the triple transgenic mouse model of AD, which develops both Aβ plaques and neurofibrillary tangles mimicking the temporal- and regional-specific profile of the human disease, suggested that impairment of the peripheral immune system and neuroimmune communication contribute to premature aging of these mice (Giménez-Llort et al., 2012). Similar cross-talk between peripheral immune cells and microglia has been described in AD and these peripheral immune cells may help in Aβ peptide clearance and modulation of microglia response (Dionisio-Santos et al., 2019). In addition, chronic neuroinflammation in normal aging (Groh et al., 2021) and age-related chronic neurodegenerative diseases, such as AD (Gate et al., 2020) and Parkinson’s disease (Galiano-Landeira et al., 2020), have been found to include innate and adaptive immune cell dysfunction (Carrasco et al., 2021; Lutshumba et al., 2021).
Thus, the intense microglial activation in chronic neurodegenerative diseases, under influence of both peripheral and central homeostatic changes, damages healthy neural tissue, and then, in response to the factors secreted by dead or dying neurons, microglial activation is chronically maintained and the associated neuroinflammation leads to progressive self-propagating damage (Xu et al., 2016; Subhramanyam et al., 2019).
Microglial activation and neuroinflammation have been shown to be modulated by voluntary exercise and EE (Duggan and Parikh, 2021), which can slow down disease progression. Indeed, we have previously demonstrated that EE and exercise in a dose-dependent way can attenuate neuroinflammation in the ME7 mouse model of prion disease (Bento-Torres et al., 2017). It has been also described that the microglial response in the 3xTg-AD mouse model is differentially modulated by voluntary wheel running and enriched environments, as evidenced by the presence of hypertrophic microglia (increased surface, volume, and somata volume) in the standard environment of laboratory cages, as compared with mice preserved in enriched cages (Rodríguez et al., 2015).
Previous consensus established that oxidative stress, DNA damage, mitochondrial dysfunction, excessive accumulation of misfolded proteins, synaptic impairment, and damage to microRNA (miRNA) processing and inflammation (Brites, 2015; Lutshumba et al., 2021) maybe associated with age-related changes in microglia (Koellhoffer et al., 2017; Costa et al., 2021; Triviño and von Bernhardi, 2021). Indeed, the immunosenescent phenotype of microglia is marked by dystrophic morphology, elevated expression of inflammatory markers, reduction in the release of neuroprotective factors, alterations in the transcriptomic profile and phagocytic activity, together with modifications in their secretome cargo (Niraula et al., 2017; Angelova and Brown, 2019; Greenwood and Brown, 2021). These alterations may explain the reduction of morphological changes in the aged ME7 prion-infected mice (Bento-Torres et al., 2017).
Astrocytes can also change their homeostatic phenotypes in response to acute and chronic pathologies, showing reactive subtypes with increased expression of the glial fibrillary acidic protein (GFAP) (Anderson et al., 2014). In the ME7 prion disease mouse model, the analysis of the hippocampal proteome revealed a predominantly activated astrocyte signature (Asuni et al., 2014).
Astrocyte reactivity in the ME7 prion disease mouse model is influenced by EE and exercise, which decreases neuroinflammation and cell reactivity (Bento-Torres et al., 2017). This is also true for AD models (Kelly, 2018). In fact, the enriched environment and physical exercise have been widely used in experimental models of chronic neurodegenerative diseases to slow the progression and to investigate the mechanisms underlying this protection (Rodríguez et al., 2011; Do et al., 2018; Kim et al., 2019; Pena et al., 2020). Exercise on the treadmill for 5 days per week reduced disease progression in the 3xTg-AD mice, which was associated with lower Aβ plaque burden and neuroinflammation, and improved mitochondrial function and neurogenesis (Kim et al., 2019). Similarly, beneficial effects were described after regular resistant training in 3xTg-AD mice with reduction of the Aβ peptide in the hippocampus and increased concentration of insulin-like growth factor 1 (IGF-1) (Pena et al., 2020). Although less explored, the Huntington’s disease mouse model R6/1HD submitted to voluntary exercise, using running wheels and subsequently enriched environment, seemed to synergistically increase hippocampal neurogenesis with old adult-generated neurons, microglia, and astrocytes, without revealing mutant huntingtin immune reactive aggregates (Ransome and Hannan, 2013).
Astrocyte reactivity by upregulation of the glial fibrillary acidic protein astrocyte reactivity in chronic neurodegenerative diseases is associated with nuclear factor kappa B (NF-κB) activation and remodeling of chromatin with subsequent transcription of proinflammatory genes (Villarreal et al., 2021). Sustained inflammatory signaling by activated microglia in to astrocytes and the established crosstalk known to exist between microglia and astrocytes induce astroglial pathological remodeling and the exacerbation of neuronal death (Jha et al., 2019; Verkhratsky et al., 2019; Matejuk and Ransohoff, 2020).
Infection and Chronic Neurodegeneration
Among the infectious diseases, there has been emerging evidence that infectious agents can be part of the environmental risk factors for the aggravation of neurological disorders (Toniolo et al., 2021a; Wouk et al., 2021). This is the case of chronic neurodegenerative disorders, such as AD (Itzhaki and Wozniak, 2010; Giridharan et al., 2019; Lopez-Rodriguez et al., 2021; Mathis et al., 2021), Parkinson’s (Munoz-Pinto et al., 2021; Rosen et al., 2021), and experimental prion diseases (Lins et al., 2016; Nazmi et al., 2019). Pre-existent inflammatory conditions, such as those associated with chronic neurodegenerative diseases in humans and mice, seem to be aggravated by both peripheral and central infections (Combrinck et al., 2002; Cunningham et al., 2005b; Holmes and Butchart, 2011; Naughton et al., 2020; Zhou et al., 2021). Indeed, cognitive deficits of patients with AD are further increased after a systemic infection, and this is preceded by an increase in the release of interleukin-1β (Holmes and Butchart, 2011). In addition, mouse prion disease shows more intense neuropathological features and faster disease progression after systemic and central endotoxin challenges (Combrinck et al., 2002; Cunningham et al., 2005b; Hennessy et al., 2015, 2017; Lins et al., 2016; Nazmi et al., 2019).
Previous findings using an intranasal Piry neurotropic virus infection, intrahippocampal injection of ME7 prion strain, or normal brain injection, demonstrated that virus-infected prion-diseased mice exhibited higher microglial morphological reactivity and more severe behavioral outcomes than ME7 prion-diseased mice not infected with virus (Lins et al., 2016). Although virus infection per se did not change the number of microglia in CA1, virus infection in prion-diseased mice (at 17 weeks post-injection) induced changes in the number and morphology of microglia. We suggested that virus infection exacerbated microglial inflammatory response in prion-infected mice, thus aggravating chronic neurodegeneration (Lins et al., 2016).
SARS-CoV-2 has been found to invade the brain via the olfactory, gustatory, and trigeminal pathways, especially at the early stage of infection (Liu J. M. et al., 2021). Its neuroinvasion route through nasal epithelium (Yachou et al., 2020) is similar to that of many other RNA viruses (Freitas et al., 2020; Awogbindin et al., 2021), including the Piry arbovirus used to infect the mouse prion disease model (de Sousa et al., 2015). We found that the Piry virus interaction with ME7-associated chronic neurodegeneration induces progressive exacerbation of microglia and astrocyte morphological alterations. These findings demand further exploration and discussion of the potential mechanisms by which microglia and astrocyte dysregulated responses (Murta et al., 2020) may contribute to post-COVID-19 neurological sequelae (Mishra and Banerjea, 2020) that are associated with the aggravation of chronic neurodegenerative diseases (Sita et al., 2021).
Neuropathological examination of many areas of the central nervous system in aged patients infected with SARS-CoV-2 who died during the disease revealed signs of neuroinflammation with astrogliosis and microglial activation. Microglial nodules and neuronophagia, most prominent in the brainstem, with hypoxic/ischemic changes in many areas of all examined brains, were also evident (Matschke et al., 2020; Thakur et al., 2021). In this study, it is important to highlight that 44% of the elderly patients also revealed neuropathological signs of ongoing neurodegenerative diseases (Thakur et al., 2021).
Following SARS-CoV-2 respiratory infection, choroid plexus epithelial cells are affected by signals from peripheral inflammation followed by activation of the immune system of the brain, such as differential expression of microglial and astrocytic inflammatory-associated genes, dysregulated homeostasis, and peripheral T-cell neuroinvasion (Schwabenland et al., 2021; Yang et al., 2021). These studies showed no molecular traces of SARS-CoV-2 in the brain, but broad cellular perturbations of the choroid plexus leading to the spread of peripheral inflammation mediators into the brain. These findings suggest that the severity of the neuropathological changes is not caused by direct infection of the virus in the brain parenchyma, but rather from systemic inflammation. Thus, it remains open the possibility that similar pathological changes in patients who survived from COVID-19 may aggravate ongoing chronic neurodegenerative diseases.
It has been noted that elderly patients infected with COVID-19, who had episodes of delirium, showed significant hyperactivation of microglia in the hippocampus. Together with the inflammatory lesions of the brainstem and the presence of topographic signs and symptoms, in the absence of specific signs of encephalitis associated with SARS-CoV-2, such features constitute the so-called COVID-19 encephalopathic syndrome (Poloni et al., 2021). While delirium in humans and sickness behavior in experimental models are transient, there is compelling evidence that such systemic immune responses and inflammation give rise to long-lasting consequences for the brain, particularly in aged individuals (Lutshumba et al., 2021). This condition of long-lasting symptoms experienced by many patients who have suffered from acute COVID infectious is now referred to as the long COVID syndrome (Hugon et al., 2021; Taribagil et al., 2021).
It is, therefore, reasonable to infer that a patient who has survived from COVID-19 encephalopathic syndrome, experiencing or not experiencing long-COVID symptoms, may suffer exacerbated neuroinflammation that will accelerate/aggravate the progression of pre-existing chronic neurodegenerative disease.
It is important to highlight, however, that although pathogenic mechanisms of age-related neurodegenerative disorders include the seeded aggregation of disease-specific proteins, as in the prion disease model (Walker and Jucker, 2015), the incomplete similarity of events observed in these diseases does require a cautionary approach to the generalized use of prion disease as a proxy for immune response investigation in all prion-like disorders (Guest et al., 2011). In addition, the possibility of differential mechanisms by which peripheral or central infections interact and aggravate abnormal disease-specific protein aggregation and damage to the brain tissue remains to be investigated in detail in each of those diseases. Finally, it is also imperative to investigate if exogenous and endogenous risk factors for each disorder interact with infections, and how this interaction contributes to misfold and progressive accumulation of protein clumps. It is expected that future studies may reveal new opportunities for therapeutics and also for new public health risk identification (Cashman, 2015).
Chronic Neurodegeneration, Virus Infection, and miRNAs
miRNAs can regulate innate and adaptive immunity by regulating microglia activation, astrocyte reactivity, and by controlling the egress of peripheral immune cells, such as neutrophils, macrophages, T cells, and B cells (Gaudet et al., 2018). miRNAs play an emerging and important role in the interplay between viruses and host cells (Liu W. et al., 2021; Pandey et al., 2021), and potential interaction between SARS-CoV-2 and human miRNAs have been predicted and tested (Marchi et al., 2021; Siniscalchi et al., 2021). Neurodegenerative diseases, such as AD, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and prion-like diseases, are characterized by the deposition of misfolded proteins, such as Aβ, tau, α-synuclein, huntingtin, and prion proteins (Khan et al., 2021). Deregulated miRNA profiles are associated with the development and progression of AD. They are known to induce the activation of microglia into disease-associated polarized phenotypes that aggravate neurodegeneration. However, the modulation of the inflammatory-associated miRNAs may also encourage microglia to engage in reparative mechanisms (Fernandes et al., 2018; Brites, 2020). The communication between microglia and astrocytes is mediated through exosomes, which are small extracellular vesicles, and by soluble factors as cytokines. Exosomes are enriched in lipids, proteins, and genetic material, and their cargo in miRNAs was shown to have an important effect on the behavior of recipient cells. Dysregulated production of miRNA has been reported to cause neuroimmune dysfunction (Yang and Zhu, 2019) and encourage neurodegenerative processes in AD mouse models and patients (Guedes et al., 2014; Brites, 2020; Kim et al., 2020). It has been proposed that the SARS-CoV-2 gene product Spike is able to modify the host exosomal cargo, thus, facilitating its transportation to distant uninfected tissues and organs initiating a severe inflammatory cascade (Mishra and Banerjea, 2021). Spike transfected cells release a significant number of exosomes enriched in miRNA(miR)-148a and miR-590 that are internalized by microglia and are able to upregulate the proinflammatory gene expression, such as tumor necrosis factor alfa (TNF-α) and interferon beta (IFN-β), which can promote the unwanted exacerbation of inflammatory microglia responses (Mishra and Banerjea, 2021).
Concluding Remarks
Social isolation, sedentary life, and infection are all associated with the restrictions imposed by the COVID-19 pandemic rules and the presence of the virus. In this study, we have revisited the effects of sedentary life and infections on mouse prion disease progression, as a proxy for the exacerbated immune response of prion-like chronic ongoing neurodegenerative diseases. Our previous study with mouse prion disease has demonstrated that these influences contribute to the undesirable aggravation of astrocyte reactivity and microglial activation, which results in more severe behavioral outcomes, and acceleration of disease progression. We anticipate that the SARSCoV-2 infection may similarly potentiate ongoing chronic neurodegenerative disease progression in patients surviving to COVID-19. Our findings, and those of other researchers, have demonstrated the benefits of EE and physical exercise, while emphasizing that an active lifestyle may reduce neuroinflammation, cognitive decline, and behavioral abnormalities and may slow disease progression. Thus, a more physically active lifestyle might also be expected to positively impact on the downstream sequelae associated with SARS-CoV-2 infection.
Author Contributions
All authors contributed substantially to the conception or design of the study; the acquisition, analysis, or interpretation of data for the study; drafting the study or revising it critically for important intellectual content; or final approval of the version to be published; and agreed to be accountable for all aspects of the study in ensuring that questions related to the accuracy or integrity of any part of the study are appropriately investigated and resolved. CWPD, DB, and DA participated in the data interpretation and writing of the final version.
Funding
CWPD was supported by the Brazilian Research Council – CNPq Grant Nos. 307749/2004-5 and 471077/2007-0, Fundação Amazônia de Amparo a Estudos e Pesquisas do Pará – FAPESPA, ICAAF No. 039/2017, Pró-Reitoria de Pesquisa e Pós-Graduação da Universidade Federal do Pará – PROPESP Edital 2021-PIAPA; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES – Pró-Amazônia, Grant No. 3311/2013. DB was supported by the Fundacção para a Ciência e a Tecnologia (PTDC/MED-NEU/31395/2017, LISBOA-01-0145-FEDER-031395, and UID/DTP/04138/2018-2021). PV was supported by the Brazilian National Research Council – CNPq Grant Nos. 573739/2008-0, 457664/2013-4, and 303999/2016-0.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Alam, M. Z., Alam, Q., Kamal, M. A., Jiman-Fatani, A. A., Azhar, E. I., Khan, M. A., et al. (2017). Infectious agents and neurodegenerative diseases: exploring the links. Curr. Top. Med. Chem. 17, 1390–1399. doi: 10.2174/1568026617666170103164040
Almutairi, M. M., Gong, C., Xu, Y. G., Chang, Y., and Shi, H. (2016). Factors controlling permeability of the blood-brain barrier. Cell. Mol. Life Sci. 73, 57–77. doi: 10.1007/s00018-015-2050-8
Alonso-Lana, S., Marquié, M., Ruiz, A., and Boada, M. (2020). Cognitive and neuropsychiatric manifestations of COVID-19 and effects on elderly individuals with dementia. Front. Aging Neurosci. 12:588872. doi: 10.3389/fnagi.2020.588872
Alpaugh, M., and Cicchetti, F. (2021). Huntington’s disease: lessons from prion disorders. J. Neurol. 268, 3493–3504. doi: 10.1007/s00415-021-10418-8
Amieva, H., Stoykova, R., Matharan, F., Helmer, C., Antonucci, T. C., and Dartigues, J. F. (2010). What aspects of social network are protective for dementia? Not the quantity but the quality of social interactions is protective up to 15 years later. Psychosom. Med. 72, 905–911. doi: 10.1097/psy.0b013e3181f5e121
Amor, S., Peferoen, L. A., Vogel, D. Y., Breur, M., van der Valk, P., Baker, D., et al. (2014). Inflammation in neurodegenerative diseases–an update. Immunology 142, 151–166. doi: 10.1111/imm.12233
Anderson, M. A., Ao, Y., and Sofroniew, M. V. (2014). Heterogeneity of reactive astrocytes. Neurosci. Lett. 565, 23–29. doi: 10.1016/j.neulet.2013.12.030
Andrew, M. K., and Rockwood, K. (2010). Social vulnerability predicts cognitive decline in a prospective cohort of older Canadians. Alzheimers Dement. 6, 319–325.e1.
Angelova, D. M., and Brown, D. R. (2019). Microglia and the aging brain: are senescent microglia the key to neurodegeneration? J. Neurochem. 151, 676–688. doi: 10.1111/jnc.14860
Annadurai, N., De Sanctis, J. B., Hajdúch, M., and Das, V. (2021). Tau secretion and propagation: perspectives for potential preventive interventions in AD and other tauopathies. Exp. Neurol. 343:113756. doi: 10.1016/j.expneurol.2021.113756
Araújo, F. C., Gonçalves, N. P., and Mourão, A. F. (2021). Impact of the mandatory confinement during the first wave of the SARS-CoV-2/COVID-19 pandemic in Portuguese patients with rheumatoid arthritis: results from the COVID in RA (COVIDRA) survey. Acta Reumatol. Port. 46, 126–133.
Armstrong, R. (2020). Cortical laminar distribution of β-amyloid deposits in five neurodegenerative disorders. Folia Neuropathol. 58, 1–9. doi: 10.5114/fn.2020.94001
Astrom, M. B., Feigh, M., and Pedersen, B. K. (2010). Persistent low-grade inflammation and regular exercise. Front. Biosci. (Schol. Ed.) 2:96–105. doi: 10.2741/s48
Asuni, A. A., Gray, B., Bailey, J., Skipp, P., Perry, V. H., and O’Connor, V. (2014). Analysis of the hippocampal proteome in ME7 prion disease reveals a predominant astrocytic signature and highlights the brain-restricted production of clusterin in chronic neurodegeneration. J. Biol. Chem. 289, 4532–4545. doi: 10.1074/jbc.m113.502690
Asuni, A. A., Perry, V. H., and O’Connor, V. (2010). Change in tau phosphorylation associated with neurodegeneration in the ME7 model of prion disease. Biochem. Soc. Trans. 38, 545–551. doi: 10.1042/bst0380545
Awogbindin, I. O., Ben-Azu, B., Olusola, B. A., Akinluyi, E. T., Adeniyi, P. A., Di Paolo, T., et al. (2021). Microglial implications in SARS-CoV-2 infection and COVID-19: lessons from viral RNA neurotropism and possible relevance to Parkinson’s disease. Front. Cell. Neurosci. 15:670298. doi: 10.3389/fncel.2021.670298
Ayers, J. I., Paras, N. A., and Prusiner, S. B. (2020). Expanding spectrum of prion diseases. Emerg. Top. Life Sci. 4, 155–167. doi: 10.1042/etls20200037
Azam, S., Haque, M. E., Kim, I. S., and Choi, D. K. (2021). Microglial turnover in ageing-related neurodegeneration: therapeutic avenue to intervene in disease progression. Cells 10:150. doi: 10.3390/cells10010150
Bailly, S., Fabre, O., Legrand, R., Pantagis, L., Mendelson, M., Terrail, R., et al. (2021). The impact of the COVID-19 lockdown on weight loss and body composition in subjects with overweight and obesity participating in a nationwide weight-loss program: impact of a remote consultation follow-up-the CO-RNPC study. Nutrients 13:2152. doi: 10.3390/nu13072152
Barguilla, A., Fernández-Lebrero, A., Estragués-Gázquez, I., García-Escobar, G., Navalpotro-Gómez, I., Manero, R. M., et al. (2020). Effects of COVID-19 pandemic confinement in patients with cognitive impairment. Front. Neurol. 11:589901. doi: 10.3389/fneur.2020.589901
Bento-Torres, J., Sobral, L. L., Reis, R. R., de Oliveira, R. B., Anthony, D. C., Vasconcelos, P. F. C., et al. (2017). Age and environment influences on mouse prion disease progression: behavioral changes and morphometry and stereology of hippocampal astrocytes. Oxid. Med. Cell. Longev. 2017:4504925.
Betmouni, S., Perry, V. H., and Gordon, J. L. (1996). Evidence for an early inflammatory response in the central nervous system of mice with scrapie. Neuroscience 74, 1–5. doi: 10.1016/0306-4522(96)00212-6
Bettinger, J., and Ghaemmaghami, S. (2020). Methionine oxidation within the prion protein. Prion 14, 193–205. doi: 10.1080/19336896.2020.1796898
Bolton, D. C., McKinley, M. P., and Prusiner, S. B. (1982). Identification of a protein that purifies with the scrapie prion. Science 218, 1309–1311. doi: 10.1126/science.6815801
Borner, R., Bento-Torres, J., Souza, D. R. V., Sadala, D. B., Trevia, N., Farias, J. A., et al. (2011). Early behavioral changes and quantitative analysis of neuropathological features in murine prion disease Stereological analysis in the albino Swiss mice model. Prion 5, 215–227. doi: 10.4161/pri.5.3.16936
Bourgonje, A. R., Abdulle, A. E., Timens, W., Hillebrands, J. L., Navis, G. J., Gordijn, S. J., et al. (2020). Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J. Pathol. 251, 228–248.
Braak, H., and Braak, E. (1991). Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol. 1, 213–216. doi: 10.1111/j.1750-3639.1991.tb00661.x
Brites, D. (2015). Cell ageing: a flourishing field for neurodegenerative diseases. AIMS Mol. Sci. 2, 225–258. doi: 10.3934/molsci.2015.3.225
Brites, D. (2020). Regulatory function of microRNAs in microglia. Glia 68, 1631–1642. doi: 10.1002/glia.23846
Brown, D. (2005). Neurodegeneration and oxidative stress: prion disease results from loss of antioxidant defence. Folia Neuropathol. 43, 229–243.
Brown, K. L., and Mabbott, N. A. (2014). Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy. J. Gen. Virol. 95, 231–243. doi: 10.1099/vir.0.058958-0
Bruce, M., McConnell, I., Fraser, H., and Dickinson, A. (1991). The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. J. Gen. Virol. 72, 595–603. doi: 10.1099/0022-1317-72-3-595
Burtscher, J., Burtscher, M., and Millet, G. P. (2021). The central role of mitochondrial fitness on antiviral defenses: an advocacy for physical activity during the COVID-19 pandemic. Redox Biol. 43:101976. doi: 10.1016/j.redox.2021.101976
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., and Alimonti, A. (2019). Cellular senescence: aging, cancer, and injury. Physiol. Rev. 99, 1047–1078. doi: 10.1152/physrev.00020.2018
Carlson, G. A., and Prusiner, S. B. (2021). How an Infection of sheep revealed prion mechanisms in AD and other neurodegenerative disorders. Int. J. Mol. Sci. 22:4861. doi: 10.3390/ijms22094861
Carod-Artal, F. J. (2020). Neurological complications of coronavirus and COVID-19. Rev. Neurol. 70, 311–322.
Carrasco, E., Gómez de Las Heras, M. M., Gabandé-Rodríguez, E., Desdín-Micó, G., Aranda, J. F., and Mittelbrunn, M. (2021). The role of T cells in age-related diseases. Nat. Rev. Immunol. [Epub ahead of print].
Carroll, J. A., and Chesebro, B. (2019). Neuroinflammation, microglia, and cell-association during Prion disease. Viruses 11:65. doi: 10.3390/v11010065
Carvalho-Paulo, D., Bento Torres Neto, J., Filho, C. S., de Oliveira, T. C. G., de Sousa, A. A., Dos Reis, R. R., et al. (2021). Microglial morphology across distantly related species: phylogenetic, environmental and age influences on microglia reactive and surveillance states. Front. Immunol. 12:683026. doi: 10.3389/fimmu.2021.683026
Cashman, N. R. (2015). Propagated protein misfolding: new opportunities for therapeutics, new public health risk. Can. Commun. Dis. Rep. 41, 196–199. doi: 10.14745/ccdr.v41i08a03
Chastin, S. F. M., Abaraogu, U., Bourgois, J. G., Dall, P. M., Darnborough, J., Duncan, E., et al. (2021). Effects of regular physical activity on the immune system, vaccination and risk of community-acquired infectious disease in the general population: systematic review and meta-analysis. Sports Med. 51, 1673–1686. doi: 10.1007/s40279-021-01466-1
Clark, A., Jit, M., Warren-Gash, C., Guthrie, B., Wang, H. H. X., Mercer, S. W., et al. (2020). Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study. Lancet Glob. Health 8, e1003–e1017.
Coll, R. C., O’Neill, L., and Schroder, K. (2016). Questions and controversies in innate immune research: what is the physiological role of NLRP3? Cell Death Discov. 2:16019.
Collinge, J. (2001). Prion diseases of humans and animals: their causes and molecular basis. Annu. Rev. Neurosci. 24, 519–550. doi: 10.1146/annurev.neuro.24.1.519
Combrinck, M. I., Perry, V. H., and Cunningham, C. (2002). Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience 112, 7–11. doi: 10.1016/s0306-4522(02)00030-1
Contiliani, D. F., Ribeiro, Y. A., de Moraes, V. N., and Pereira, T. C. (2021). MicroRNAs in prion diseases-from molecular mechanisms to insights in translational medicine. Cells 10:1620. doi: 10.3390/cells10071620
Costa, J., Martins, S., Ferreira, P. A., Cardoso, A. M. S., Guedes, J. R., Peça, J., et al. (2021). The old guard: age-related changes in microglia and their consequences. Mech. Ageing Dev. 197:111512. doi: 10.1016/j.mad.2021.111512
Cunha, L. L., Perazzio, S. F., Azzi, J., Cravedi, P., and Riella, L. V. (2020). Remodeling of the immune response with aging: immunosenescence and its potential impact on COVID-19 immune response. Front. Immunol. 11:1748. doi: 10.3389/fimmu.2020.01748
Cunningham, C. (2005). “Mouse behavioral studies and what they can teach us about prion diseses,” in Neurodegeneration and Prion Disese, ed. D. Brown (New York, NY: Springer Science + Business Media, Inc), 111–137. doi: 10.1007/0-387-23923-5_5
Cunningham, C., Deacon, R. M., Chan, K., Boche, D., Rawlins, J. N., and Perry, V. H. (2005a). Neuropathologically distinct prion strains give rise to similar temporal profiles of behavioral deficits. Neurobiol. Dis. 18, 258–269. doi: 10.1016/j.nbd.2004.08.015
Cunningham, C., Wilcockson, D. C., Campion, S., Lunnon, K., and Perry, V. H. (2005b). Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J. Neurosci. 25, 9275–9284. doi: 10.1523/jneurosci.2614-05.2005
Daffner, K. R. (2010). Promoting successful cognitive aging: a comprehensive review. J. Alzheimers Dis. 19, 1101–1122. doi: 10.3233/jad-2010-1306
de Boer, D. R., Hoekstra, F., Huetink, K. I. M., Hoekstra, T., Krops, L. A., and Hettinga, F. J. (2021). Physical activity, sedentary behavior and well-being of adults with physical disabilities and/or chronic diseases during the first wave of the COVID-19 pandemic: a rapid review. Int. J. Environ. Res. Public Health 18:6342. doi: 10.3390/ijerph18126342
de Freitas, G. B., Lourenco, M. V., and De Felice, F. G. (2020). Protective actions of exercise-related FNDC5/Irisin in memory and AD. J. Neurochem. 155, 602–611. doi: 10.1111/jnc.15039
de Sousa, A. A., dos Reis, R. R., de Lima, C. M., de Oliveira, M. A., Fernandes, T. N., Gomes, G. F., et al. (2015). Three-dimensional morphometric analysis of microglial changes in a mouse model of virus encephalitis: age and environmental influences. Eur. J. Neurosci. 42, 2036–2050. doi: 10.1111/ejn.12951
Deacon, R., Raley, J., Perry, V., and Rawlins, J. (2001). Burrowing into prion diasease. Neuroreport 12, 2053–2057. doi: 10.1097/00001756-200107030-00052
Deacon, R. M. J. (2009). Burrowing: a sensitive behavioural assay, tested in five species of laboratory rodents. Behav. Brain Res. 200, 128–133. doi: 10.1016/j.bbr.2009.01.007
DeArmond, S. J. (1993). AD and Creutzfeldt-Jakob disease: overlap of pathogenic mechanisms. Curr. Opin. Neurol. 6, 872–881. doi: 10.1097/00019052-199312000-00008
DeArmond, S. J., McKinley, M. P., Barry, R. A., Braunfeld, M. B., McColloch, J. R., and Prusiner, S. B. (1985). Identification of prion amyloid filaments in scrapie-infected brain. Cell 41, 221–235. doi: 10.1016/0092-8674(85)90076-5
Dewanjee, S., Vallamkondu, J., Kalra, R. S., Puvvada, N., Kandimalla, R., and Reddy, P. H. (2021). Emerging COVID-19 neurological manifestations: present outlook and potential neurological challenges in COVID-19 pandemic. Mol. Neurobiol. 58, 4694–4715. doi: 10.1007/s12035-021-02450-6
Diack, A. B., Alibhai, J. D., Barron, R., Bradford, B., Piccardo, P., and Manson, J. C. (2016). Insights into mechanisms of chronic neurodegeneration. Int. J. Mol. Sci. 17:82.
Dinakaran, D., Manjunatha, N., Naveen Kumar, C., and Suresh, B. M. (2020). Neuropsychiatric aspects of COVID-19 pandemic: a selective review. Asian J. Psychiatr. 53:102188. doi: 10.1016/j.ajp.2020.102188
Dionisio-Santos, D. A., Olschowka, J. A., and O’Banion, M. K. (2019). Exploiting microglial and peripheral immune cell crosstalk to treat AD. J Neuroinflammation 16:74.
Do, K., Laing, B. T., Landry, T., Bunner, W., Mersaud, N., Matsubara, T., et al. (2018). The effects of exercise on hypothalamic neurodegeneration of AD mouse model. PLoS One 13:e0190205. doi: 10.1371/journal.pone.0190205
do Brito Valente, A. F., Jaspers, R. T., and Wüst, R. C. (2021). Regular physical exercise mediates the immune response in atherosclerosis. Exerc. Immunol. Rev. 27, 42–53.
Duggan, M. R., and Parikh, V. (2021). Microglia and modifiable life factors: potential contributions to cognitive resilience in aging. Behav. Brain Res. 405:113207. doi: 10.1016/j.bbr.2021.113207
Dye, L., Boyle, N. B., Champ, C., and Lawton, C. (2017). The relationship between obesity and cognitive health and decline. Proc. Nutr. Soc. 76, 443–454. doi: 10.1017/s0029665117002014
Eikelenboom, P., Bate, C., Van Gool, W. A., Hoozemans, J. J. M., Rozemuller, J. M., Veerhuis, R., et al. (2002). Neuroin?ammation in Alzheimer’s disease and Prion disease. Glia 40, 232–239.
Eikelenboom, P., Zhan, S. S., van Gool, W. A., and Allsop, D. (1994). Inflammatory mechanisms in AD. Trends Pharmacol. Sci. 15, 447–450.
Engels, E. S., Mutz, M., Demetriou, Y., and Reimers, A. K. (2021). Levels of physical activity in four domains and affective wellbeing before and during the Covid-19 pandemic. Arch. Public Health 79:122.
Faherty, C. J., Raviie Shepherd, K., Herasimtschuk, A., and Smeyne, R. J. (2005). Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism. Brain Res. Mol. Brain Res. 134, 170–179. doi: 10.1016/j.molbrainres.2004.08.008
Fernandes, A., Ribeiro, A. R., Monteiro, M., Garcia, G., Vaz, A. R., and Brites, D. (2018). Secretome from SH-SY5Y APP. Biochimie 155, 67–82.
Fernández-Borges, N., Eraña, H., Venegas, V., Elezgarai, S. R., Harrathi, C., and Castilla, J. (2015). Animal models for prion-like diseases. Virus Res. 207, 5–24. doi: 10.1016/j.virusres.2015.04.014
Fiani, B., Covarrubias, C., Desai, A., Sekhon, M., and Jarrah, R. (2020). A contemporary review of neurological sequelae of COVID-19. Front. Neurol. 11:640. doi: 10.3389/fneur.2020.00640
Filgueira, T. O., Castoldi, A., Santos, L. E. R., de Amorim, G. J., de Sousa Fernandes, M. S., Anastácio, W. L. D. N., et al. (2021). The relevance of a physical active lifestyle and physical fitness on immune defense: mitigating disease burden, with focus on COVID-19 consequences. Front. Immunol. 12:587146. doi: 10.3389/fimmu.2021.587146
Fraser, H., Bruce, M. E., McBride, P. A., and Scott, J. R. (1989). The molecular pathology of scrapie and the biological basis of lesion targeting. Prog. Clin. Biol. Res. 317, 637–644.
Fraser, H., and Dickinson, A. G. (1970). Pathogenesis of scrapie in the mouse: the role of the spleen. Nature 226, 462–463. doi: 10.1038/226462a0
Freitas, P. D. S. L., Lima, A. V. L., Carvalho, K. G. B., Cabral, T. D. S., Farias, A. M., Rodrigues, A. P. D., et al. (2020). Limbic encephalitis brain damage induced by cocal virus in adult mice is reduced by environmental enrichment: neuropathological and behavioral studies. Viruses 13:48. doi: 10.3390/v13010048
Friedler, B., Crapser, J., and McCullough, L. (2015). One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition. Acta Neuropathol. 129, 493–509. doi: 10.1007/s00401-014-1377-9
Fülöp, T., Dupuis, G., Witkowski, J. M., and Larbi, A. (2016). The role of immunosenescence in the development of age-related diseases. Rev. Invest. Clin. 68, 84–91.
Gabarre, P., Dumas, G., Dupont, T., Darmon, M., Azoulay, E., and Zafrani, L. (2020). Acute kidney injury in critically ill patients with COVID-19. Intensive Care Med. 46, 1339–1348.
Galiano-Landeira, J., Torra, A., Vila, M., and Bové, J. (2020). CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease. Brain 143, 3717–3733. doi: 10.1093/brain/awaa269
Gate, D., Saligrama, N., Leventhal, O., Yang, A. C., Unger, M. S., Middeldorp, J., et al. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in AD. Nature 577, 399–404. doi: 10.1038/s41586-019-1895-7
Gaudet, A. D., Fonken, L. K., Watkins, L. R., Nelson, R. J., and Popovich, P. G. (2018). MicroRNAs: roles in regulating neuroinflammation. Neuroscientist 24, 221–245. doi: 10.1177/1073858417721150
Giménez-Llort, L., Maté, I., Manassra, R., Vida, C., and De la Fuente, M. (2012). Peripheral immune system and neuroimmune communication impairment in a mouse model of AD. Ann. N. Y. Acad. Sci. 1262, 74–84. doi: 10.1111/j.1749-6632.2012.06639.x
Giridharan, V. V., Masud, F., Petronilho, F., Dal-Pizzol, F., and Barichello, T. (2019). Infection-induced systemic inflammation is a potential driver of AD progression. Front. Aging Neurosci. 11:122.
Goedert, M. (2020). Tau proteinopathies and the prion concept. Prog. Mol. Biol. Transl. Sci. 175, 239–259. doi: 10.1016/bs.pmbts.2020.08.003
Gómez-Nicola, D., Fransen, N. L., Suzzi, S., and Perry, V. H. (2013). Regulation of microglial proliferation during chronic neurodegeneration. J. Neurosci. 33, 2481–2493. doi: 10.1523/jneurosci.4440-12.2013
Greenwood, E. K., and Brown, D. R. (2021). Senescent microglia: the key to the ageing brain? Int. J. Mol. Sci. 22:4402. doi: 10.3390/ijms22094402
Groh, J., Knöpper, K., Arampatzi, P., Yuan, X., Lößlein, L., Saliba, A.-E., et al. (2021). Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nat. Aging 1, 357–367. doi: 10.1038/s43587-021-00049-z
Guedes, J. R., Custodia, C. M., Silva, R. J., de Almeida, L. P., Pedroso de Lima, M. C., and Cardoso, A. L. (2014). Early miR-155 upregulation contributes to neuroinflammation in AD triple transgenic mouse model. Hum. Mol. Genet. 23, 6286–6301. doi: 10.1093/hmg/ddu348
Guest, W. C., Silverman, J. M., Pokrishevsky, E., O’Neill, M. A., Grad, L. I., and Cashman, N. R. (2011). Generalization of the prion hypothesis to other neurodegenerative diseases: an imperfect fit. J. Toxicol. Environ. Health A 74, 1433–1459. doi: 10.1080/15287394.2011.618967
Guo, L., An, L., Luo, F., and Yu, B. (2020). Social isolation, loneliness and functional disability in Chinese older women and men: a longitudinal study. Age Ageing 50, 1–7. doi: 10.1080/13607863.2021.1976723
Hajek, A., Brettschneider, C., Eisele, M., Mallon, T., Oey, A., Wiese, B., et al. (2021). Social support and functional decline in the oldest old. Gerontology 1–9. doi: 10.1159/000516077 [Epub ahead of print].
Hammoudeh, S. M., Hammoudeh, A. M., Bhamidimarri, P. M., Al Safar, H., Mahboub, B., Künstner, A., et al. (2021). Systems immunology analysis reveals the contribution of pulmonary and extrapulmonary tissues to the immunopathogenesis of severe COVID-19 patients. Front. Immunol. 12:595150. doi: 10.3389/fimmu.2021.595150
Harischandra, D. S., Kondru, N., Martin, D. P., Kanthasamy, A., Jin, H., Anantharam, V., et al. (2014). Role of proteolytic activation of protein kinase Cδ in the pathogenesis of prion disease. Prion 8, 143–153. doi: 10.4161/pri.28369
Hassanein, M., Radhakrishnan, Y., Sedor, J., Vachharajani, T., Vachharajani, V. T., Augustine, J., et al. (2020). COVID-19 and the kidney. Cleve. Clin. J. Med. 87, 619–631.
He, Y., Wang, J., Ren, J., Zhao, Y., Chen, J., and Chen, X. (2021). Effect of COVID-19 on male reproductive system–a systematic review. Front. Endocrinol. (Lausanne) 12:677701. doi: 10.3389/fendo.2021.677701
Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., et al. (2015). Neuroinflammation in AD. Lancet Neurol. 14, 388–405.
Heneka, M. T., and O’Banion, M. K. (2007). Inflammatory processes in AD. J. Neuroimmunol. 184, 69–91.
Heneka, M. T., O’Banion, M. K., Terwel, D., and Kummer, M. P. (2010). Neuroinflammatory processes in AD. J. Neural. Transm. 117, 919–947.
Hennessy, E., Gormley, S., Lopez-Rodriguez, A. B., Murray, C., and Cunningham, C. (2017). Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration. Brain Behav. Immun. 59, 233–244. doi: 10.1016/j.bbi.2016.09.011
Hennessy, E., and Griffin, É, and Cunningham, C. (2015). Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNF-α. J. Neurosci. 35, 8411–8422. doi: 10.1523/jneurosci.2745-14.2015
Hilton, K. J., Cunningham, C., Reynolds, R. A., and Perry, V. H. (2013). Early hippocampal synaptic loss precedes neuronal loss and associates with early behavioural deficits in three distinct strains of Prion disease. PLoS One 8:e68062. doi: 10.1371/journal.pone.0068062
Hockly, E., Cordery, P. M., Woodman, B., Mahal, A., van Dellen, A., Blakemore, C., et al. (2002). Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann. Neurol. 51, 235–242. doi: 10.1002/ana.10094
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8.
Holbrook, J. A., Jarosz-Griffiths, H. H., Caseley, E., Lara-Reyna, S., Poulter, J. A., Williams-Gray, C. H., et al. (2021). Neurodegenerative disease and the NLRP3 inflammasome. Front. Pharmacol. 12:643254. doi: 10.3389/fphar.2021.643254
Holmes, C., and Butchart, J. (2011). Systemic inflammation and AD. Biochem. Soc. Trans. 39, 898–901.
Holmes, C., Cunningham, C., Zotova, E., Culliford, D., and Perry, V. H. (2011). Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology 77, 212–218. doi: 10.1212/wnl.0b013e318225ae07
Holt-Lunstad, J. (2018). Why social relationships are important for physical health: a systems approach to understanding and modifying risk and protection. Annu. Rev. Psychol. 69, 437–458.
Hosseini, S., Michaelsen-Preusse, K., Schughart, K., and Korte, M. (2021). Long-term consequence of non-neurotropic H3N2 influenza A virus infection for the progression of AD symptoms. Front. Cell. Neurosci. 15:643650. doi: 10.3389/fncel.2021.643650
House, J. S. (2001). Social isolation kills, but how and why? Psychosom. Med. 63, 273–274. doi: 10.1097/00006842-200103000-00011
House, J. S., Landis, K. R., and Umberson, D. (1988). Social relationships and health. Science 241, 540–545.
Huang, Z., Guo, Y., Ruan, Y., Sun, S., Lin, T., Ye, J., et al. (2020). Associations of lifestyle factors with cognition in community-dwelling adults aged 50 and older: a longitudinal cohort study. Front. Aging Neurosci. 12:601487. doi: 10.3389/fnagi.2020.601487
Hughes, D., and Halliday, M. (2017). What is our current understanding of PrP. Pathogens 6:63. doi: 10.3390/pathogens6040063
Hugon, J., Msika, E. F., Queneau, M., Farid, K., and Paquet, C. (2021). Long COVID: cognitive complaints (brain fog) and dysfunction of the cingulate cortex. J. Neurol. 1–3. [Epub ahead of print].
Idrees, D., and Kumar, V. (2021). SARS-CoV-2 spike protein interactions with amyloidogenic proteins: potential clues to neurodegeneration. Biochem. Biophys. Res. Commun. 554, 94–98. doi: 10.1016/j.bbrc.2021.03.100
Itzhaki, R. F., and Wozniak, M. A. (2010). AD and infection: do infectious agents contribute to progression of AD? Alzheimers Dement. 6, 83–84; author reply 85.
Jadavji, N. M., Kolb, B., and Metz, G. A. (2006). Enriched environment improves motor function in intact and unilateral dopamine-depleted rats. Neuroscience 140, 1127–1138. doi: 10.1016/j.neuroscience.2006.03.027
Jeffrey, M., Halliday, W. G., Bell, J., Johnston, A. R., MacLeod, N. K., Ingham, C., et al. (2000). Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie infected murine hippocampus. Neuropathol. Appl. Neurobiol. 26, 41–54. doi: 10.1046/j.1365-2990.2000.00216.x
Jha, M. K., Jo, M., Kim, J. H., and Suk, K. (2019). Microglia-astrocyte crosstalk: an intimate molecular conversation. Neuroscientist 25, 227–240. doi: 10.1177/1073858418783959
Jothimani, D., Venugopal, R., Abedin, M. F., Kaliamoorthy, I., and Rela, M. (2020). COVID-19 and the liver. J. Hepatol. 73, 1231–1240.
Karelina, K., and DeVries, A. C. (2011). Modeling social influences on human health. Psychosom. Med. 73, 67–74. doi: 10.1097/psy.0b013e3182002116
Kelly, Á (2018). Exercise-induced modulation of neuroinflammation in models of AD. Brain Plast. 4, 81–94. doi: 10.3233/bpl-180074
Khan, I., Preeti, K., Fernandes, V., Khatri, D. K., and Singh, S. B. (2021). Role of MicroRNAs, aptamers in neuroinflammation and neurodegenerative disorders. Cell. Mol. Neurobiol. [Epub ahead of print].
Kim, D., Cho, J., and Kang, H. (2019). Protective effect of exercise training against the progression of AD in 3xTg-AD mice. Behav. Brain Res. 374:112105. doi: 10.1016/j.bbr.2019.112105
Kim, E., Otgontenger, U., Jamsranjav, A., and Kim, S. S. (2020). Deleterious alteration of glia in the brain of AD. Int. J. Mol. Sci. 21:6676. doi: 10.3390/ijms21186676
Koellhoffer, E. C., McCullough, L. D., and Ritzel, R. M. (2017). Old maids: aging and its impact on microglia function. Int. J. Mol. Sci. 18:769. doi: 10.3390/ijms18040769
Krivanek, T. J., Gale, S. A., McFeeley, B. M., Nicastri, C. M., and Daffner, K. R. (2021). Promoting successful cognitive aging: a ten-year update. J. Alzheimers Dis. 81, 871–920. doi: 10.3233/jad-201462
Krueger, K. R., Wilson, R. S., Kamenetsky, J. M., Barnes, L. L., Bienias, J. L., and Bennett, D. A. (2009). Social engagement and cognitive function in old age. Exp. Aging Res. 35, 45–60.
Kudryavtseva, A. V., Krasnov, G. S., Dmitriev, A. A., Alekseev, B. Y., Kardymon, O. L., Sadritdinova, A. F., et al. (2016). Mitochondrial dysfunction and oxidative stress in aging and cancer. Oncotarget 7, 44879–44905.
Kullmann, S., Heni, M., Hallschmid, M., Fritsche, A., Preissl, H., and Häring, H. U. (2016). Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol. Rev. 96, 1169–1209. doi: 10.1152/physrev.00032.2015
Lazarov, O., Robinson, J., Tang, Y. P., Hairston, I. S., Korade-Mirnics, Z., Lee, V. M., et al. (2005). Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120, 701–713. doi: 10.1016/j.cell.2005.01.015
Lee, A. C., Tse Li, W., Apostol, L., Ma, J., Taub, P. R., Chang, E. Y., et al. (2021). Cardiovascular, cerebrovascular, and renal co-morbidities in COVID-19 patients: a systematic-review and meta-analysis. Comput. Struct. Biotechnol. J. 19, 3755–3764. doi: 10.1016/j.csbj.2021.06.038
Lee, B., Shin, M., Park, Y., Won, S. Y., and Cho, K. S. (2021). Physical exercise-induced myokines in neurodegenerative diseases. Int. J. Mol. Sci. 22:5795. doi: 10.3390/ijms22115795
Lee, I. C., Huo, T. I., and Huang, Y. H. (2020). Gastrointestinal and liver manifestations in patients with COVID-19. J. Chin. Med. Assoc. 83, 521–523. doi: 10.1097/jcma.0000000000000319
Levin, A. T., Hanage, W. P., Owusu-Boaitey, N., Cochran, K. B., Walsh, S. P., and Meyerowitz-Katz, G. (2020). Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. Eur. J. Epidemiol. 35, 1123–1138.
Li, W., Huang, E., and Gao, S. (2017). Type 1 diabetes mellitus and cognitive impairments: a systematic review. J. Alzheimers Dis. 57, 29–36. doi: 10.3233/jad-161250
Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., et al. (2018). Oxidative stress, aging, and diseases. Clin. Interv. Aging 13, 757–772.
Lins, N., Mourao, L., Trevia, N., Passos, A., Farias, J. A., Assuncao, J., et al. (2016). Virus infections on prion diseased mice exacerbate inflammatory microglial response. Oxid. Med. Cell. Long. 2016:3974648.
Liu, J. M., Tan, B. H., Wu, S., Gui, Y., Suo, J. L., and Li, Y. C. (2021). Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement, in the lethality of SARS-CoV-2 infection. J. Med. Virol. 93, 1304–1313. doi: 10.1002/jmv.26570
Liu, T., Zhang, L., Joo, D., and Sun, S. C. (2017). NF-κB signaling in inflammation. Signal Transduct. Target Ther. 2:17023.
Liu, W., He, X., and Huang, F. (2021). Analysis of serum MicroRNA-122 expression at different stages of chronic hepatitis B virus infection. Biomed. Res. Int. 2021:9957440.
López-Ortiz, S., Pinto-Fraga, J., Valenzuela, P. L., Martín-Hernández, J., Seisdedos, M. M., García-López, O., et al. (2021). Physical exercise and AD: effects on pathophysiological molecular pathways of the disease. Int. J. Mol. Sci. 22:2897. doi: 10.3390/ijms22062897
Lopez-Rodriguez, A. B., Hennessy, E., Murray, C. L., Nazmi, A., Delaney, H. J., Healy, D., et al. (2021). Acute systemic inflammation exacerbates neuroinflammation in AD: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimers Dement. [Epub ahead of print].
Lutshumba, J., Nikolajczyk, B. S., and Bachstetter, A. D. (2021). Dysregulation of systemic immunity in aging and dementia. Front. Cell. Neurosci. 15:652111. doi: 10.3389/fncel.2021.652111
Lyman, M., Lloyd, D. G., Ji, X., Vizcaychipi, M. P., and Ma, D. (2013). Neuroinflammation: the role and consequences. Neurosci. Res. 79, 1–12. doi: 10.1016/j.neures.2013.10.004
Mabbott, N. A., Bradford, B. M., Pal, R., Young, R., and Donaldson, D. S. (2020). The effects of immune system modulation on prion disease susceptibility and pathogenesis. Int. J. Mol. Sci. 21:7299. doi: 10.3390/ijms21197299
Manca, R., De Marco, M., and Venneri, A. (2020). The impact of COVID-19 infection and enforced prolonged social isolation on neuropsychiatric symptoms in older adults with and without dementia: a review. Front. Psychiatry 11:585540. doi: 10.3389/fpsyt.2020.585540
Marchi, R., Sugita, B., Centa, A., Fonseca, A. S., Bortoletto, S., Fiorentin, K., et al. (2021). The role of microRNAs in modulating SARS-CoV-2 infection in human cells: a systematic review. Infect. Genet. Evol. 91:104832. doi: 10.1016/j.meegid.2021.104832
Marques Zilli, E., O’Donnell, A., Salinas, J., Aparicio, H. J., Gonzales, M. M., Jacob, M., et al. (2021). Herpes labialis, Chlamydophila pneumoniae, Helicobacter pylori, and Cytomegalovirus infections and risk of dementia: the Framingham heart study. J. Alzheimers Dis. 82, 593–605. doi: 10.3233/jad-200957
Martinez, F., Novarino, J., Mejía, J. E., Fazilleau, N., and Aloulou, M. (2021). Ageing of T-dependent B cell responses. Immunol. Lett. 233, 97–103. doi: 10.1016/j.imlet.2021.03.012
Matejuk, A., and Ransohoff, R. M. (2020). Crosstalk between astrocytes and microglia: an overview. Front. Immunol. 11:1416.
Mathis, S. P., Bodduluri, S. R., and Haribabu, B. (2021). Interrelationship between the 5-lipoxygenase pathway and microbial dysbiosis in the progression of AD. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1866:158982. doi: 10.1016/j.bbalip.2021.158982
Mathot, E., Liberman, K., Cao Dinh, H., Njemini, R., and Bautmans, I. (2021). Systematic review on the effects of physical exercise on cellular immunosenescence-related markers–an update. Exp. Gerontol. 149:111318. doi: 10.1016/j.exger.2021.111318
Matschke, J., Lütgehetmann, M., Hagel, C., Sperhake, J. P., Schröder, A. S., Edler, C., et al. (2020). Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 19, 919–929. doi: 10.1016/s1474-4422(20)30308-2
McBride, P. A., Wilson, M. I., Eikelenboom, P., Tunstall, A., and Bruce, M. E. (1998). Heparan sulfate proteoglycan is associated with amyloid plaques and neuroanatomically targeted PrP pathology throughout the incubation period of scrapie-infected mice. Exp. Neurol. 149, 447–454. doi: 10.1006/exnr.1997.6740
McQuaid, C., Brady, M., and Deane, R. (2021). SARS-CoV-2: is there neuroinvasion? Fluids Barriers CNS 18:32.
Mendonça, D. C. B., Fernandes, D. R., Hernandez, S. S., Soares, F. D. G., Figueiredo, K., and Coelho, F. G. M. (2021). Physical exercise is effective for neuropsychiatric symptoms in AD: a systematic review. Arq. Neuropsiquiatr. 79, 447–456. doi: 10.1590/0004-282x-anp-2020-0284
Meyerowitz-Katz, G., and Merone, L. (2020). A systematic review and meta-analysis of published research data on COVID-19 infection fatality rates. Int. J. Infect. Dis. 101, 138–148.
Mishra, R., and Banerjea, A. C. (2020). Neurological damage by coronaviruses: a catastrophe in the queue! Front. Immunol. 11:565521. doi: 10.3389/fimmu.2020.565521
Mishra, R., and Banerjea, A. C. (2021). SARS-CoV-2 spike targets USP33-IRF9 axis. Front. Immunol. 12:656700. doi: 10.3389/fimmu.2021.656700
Morris, R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47–60. doi: 10.1016/0165-0270(84)90007-4
Morris, R. G., Garrud, P., Rawlins, J. N., and O’Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683. doi: 10.1038/297681a0
Müller, L., Di Benedetto, S., and Pawelec, G. (2019). The immune system and its dysregulation with aging. Subcell. Biochem. 91, 21–43. doi: 10.1007/978-981-13-3681-2_2
Munoz-Pinto, M. F., Empadinhas, N., and Cardoso, S. M. (2021). The neuromicrobiology of Parkinson’s disease: a unifying theory. Ageing Res. Rev. 70:101396.
Murta, V., Villarreal, A., and Ramos, A. J. (2020). Severe acute respiratory syndrome coronavirus 2 impact on the central nervous system: are astrocytes and microglia main players or merely bystanders? ASN Neuro 12:1759091420954960.
Nagu, P., Parashar, A., Behl, T., and Mehta, V. (2021). CNS implications of COVID-19: a comprehensive review. Rev. Neurosci. 32, 219–234.
Naughton, S. X., Raval, U., and Pasinetti, G. M. (2020). Potential novel role of COVID-19 in AD and preventative mitigation strategies. J. Alzheimers Dis. 76, 21–25. doi: 10.3233/jad-200537
Nazmi, A., Field, R. H., Griffin, E. W., Haugh, O., Hennessy, E., Cox, D., et al. (2019). Chronic neurodegeneration induces type I interferon synthesis via STING, shaping microglial phenotype and accelerating disease progression. Glia 67, 1254–1276. doi: 10.1002/glia.23592
Niraula, A., Sheridan, J. F., and Godbout, J. P. (2017). Microglia priming with aging and stress. Neuropsychopharmacology 42, 318–333. doi: 10.1038/npp.2016.185
Noguchi, T., Kubo, Y., Hayashi, T., Tomiyama, N., Ochi, A., and Hayashi, H. (2021). Social isolation and self-reported cognitive decline among older adults in Japan: a longitudinal study in the COVID-19 pandemic. J. Am. Med. Dir. Assoc. 22, 1352–1356.e2.
Obst, J., Simon, E., Mancuso, R., and Gomez-Nicola, D. (2017). The role of microglia in prion diseases: a paradigm of functional diversity. Front. Aging Neurosci. 9:207. doi: 10.3389/fnagi.2017.00207
Orge, L., Lima, C., Machado, C., Tavares, P., Mendonça, P., Carvalho, P., et al. (2021). Neuropathology of animal prion diseases. Biomolecules 11:466.
Pandey, N., Rastogi, M., and Singh, S. K. (2021). Chandipura virus dysregulates the expression of hsa-miR-21-5p to activate NF-κB in human microglial cells. J. Biomed. Sci. 28:52.
Pannone, G., Caponio, V. C. A., De Stefano, I. S., Ramunno, M. A., Meccariello, M., Agostinone, A., et al. (2021). Lung histopathological findings in COVID-19 disease–a systematic review. Infect. Agent Cancer 16:34.
Patel, K. P., Patel, P. A., Vunnam, R. R., Hewlett, A. T., Jain, R., Jing, R., et al. (2020). Gastrointestinal, hepatobiliary, and pancreatic manifestations of COVID-19. J. Clin. Virol. 128:104386. doi: 10.1016/j.jcv.2020.104386
Pawelec, G. (2018). Age and immunity: what is “immunosenescence”? Exp. Gerontol. 105, 4–9. doi: 10.1016/j.exger.2017.10.024
Pedersen, B. K. (2009). Edward F. Adolph distinguished lecture: muscle as an endocrine organ: IL-6 and other myokines. J. Appl. Physiol. 107, 1006–1014. doi: 10.1152/japplphysiol.00734.2009
Peggion, C., Stella, R., Lorenzon, P., Spisni, E., Bertoli, A., and Massimino, M. L. (2020). Microglia in Prion diseases: angels or demons? Int. J. Mol. Sci. 21:7765. doi: 10.3390/ijms21207765
Pena, G. S., Paez, H. G., Johnson, T. K., Halle, J. L., Carzoli, J. P., Visavadiya, N. P., et al. (2020). Hippocampal growth factor and myokine cathepsin B expression following aerobic and resistance training in 3xTg-AD Mice. Int. J. Chronic Dis. 2020:5919501.
Perry, V. H. (2010). Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol. 120, 277–286. doi: 10.1007/s00401-010-0722-x
Petersen, A. M., and Pedersen, B. K. (2005). The anti-inflammatory effect of exercise. J. Appl. Physiol. (1985) 98, 1154–1162.
Pietropaolo, S., Sun, Y., Li, R., Brana, C., Feldon, J., and Yee, B. K. (2009). Limited impact of social isolation on Alzheimer-like symptoms in a triple transgenic mouse model. Behav. Neurosci. 123, 181–195. doi: 10.1037/a0013607
Poloni, T. E., Medici, V., Moretti, M., Visonà, S. D., Cirrincione, A., Carlos, A. F., et al. (2021). COVID-19-related neuropathology and microglial activation in elderly with and without dementia. Brain Pathol. 31:e12997.
Priola, S. A. (2017). Cell biology approaches to studying prion diseases. Methods Mol. Biol. 1658, 83–94. doi: 10.1007/978-1-4939-7244-9_7
Proschinger, S., Winker, M., Joisten, N., Bloch, W., Palmowski, J., and Zimmer, P. (2021). The effect of exercise on regulatory T cells: a systematic review of human and animal studies with future perspectives and methodological recommendations. Exerc. Immunol. Rev. 27, 142–166.
Prusiner, S. B. (1982). Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144. doi: 10.1126/science.6801762
Prusiner, S. B. (1996). Molecular biology and pathogenesis of prion diseases. Trends Biochem. Sci. 21, 482–487.
Ransohoff, R. M. (2016). How neuroinflammation contributes to neurodegeneration. Science 353, 777–783. doi: 10.1126/science.aag2590
Ransohoff, R. M., and Perry, V. H. (2009). Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119–145. doi: 10.1146/annurev.immunol.021908.132528
Ransome, M. I., and Hannan, A. J. (2013). Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD mice. Mol. Cell. Neurosci. 54, 93–107. doi: 10.1016/j.mcn.2013.01.005
Reis, R., Hennessy, E., Murray, C., and Griffin, É, and Cunningham, C. (2015). At the centre of neuronal, synaptic and axonal pathology in murine prion disease: degeneration of neuroanatomically linked thalamic and brainstem nuclei. Neuropathol. Appl. Neurobiol. 41, 780–797. doi: 10.1111/nan.12232
Ritchie, D. L., and Barria, M. A. (2021). Prion diseases: a unique transmissible agent or a model for neurodegenerative diseases? Biomolecules 11:207. doi: 10.3390/biom11020207
Rodríguez, J. J., Noristani, H. N., Olabarria, M., Fletcher, J., Somerville, T. D., Yeh, C. Y., et al. (2011). Voluntary running and environmental enrichment restores impaired hippocampal neurogenesis in a triple transgenic mouse model of AD. Curr. Alzheimer Res. 8, 707–717. doi: 10.2174/156720511797633214
Rodríguez, J. J., Noristani, H. N., and Verkhratsky, A. (2015). Microglial response to AD is differentially modulated by voluntary wheel running and enriched environments. Brain Struct. Funct. 220, 941–953. doi: 10.1007/s00429-013-0693-5
Ronco, C., Reis, T., and Husain-Syed, F. (2020). Management of acute kidney injury in patients with COVID-19. Lancet Respir. Med. 8, 738–742.
Rosen, B., Kurtishi, A., Vazquez-Jimenez, G. R., and Møller, S. G. (2021). The Intersection of Parkinson’s Disease, Viral Infections, and COVID-19. Mol Neurobiol. 58, 4477–4486.
Saczynski, J. S., Pfeifer, L. A., Masaki, K., Korf, E. S., Laurin, D., White, L., et al. (2006). The effect of social engagement on incident dementia: the Honolulu-Asia Aging Study. Am. J. Epidemiol. 163, 433–440.
Salman, A., Sigodo, K. O., Al-Ghadban, F., Al-Lahou, B., Alnashmi, M., Hermassi, S., et al. (2021). Effects of COVID-19 lockdown on physical activity and dietary behaviors in kuwait: a cross-sectional study. Nutrients 13:2252. doi: 10.3390/nu13072252
Scheckel, C., and Aguzzi, A. (2018). Prions, prionoids and protein misfolding disorders. Nat. Rev. Genet. 19, 405–418. doi: 10.1038/s41576-018-0011-4
Schmeer, C., Kretz, A., Wengerodt, D., Stojiljkovic, M., and Witte, O. W. (2019). Dissecting aging and senescence-current concepts and open lessons. Cells 8:1446. doi: 10.3390/cells8111446
Schwabenland, M., Salié, H., Tanevski, J., Killmer, S., Lago, M. S., Schlaak, A. E., et al. (2021). Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity 54, 1594–1610.e11.
Scott, J. R., Davies, D., and Fraser, H. (1992). Scrapie in the central nervous system: neuroanatomical spread of infection and Sinc control of pathogenesis. J. Gen. Virol. 73(Pt 7), 1637–1644. doi: 10.1099/0022-1317-73-7-1637
Sellami, M., Bragazzi, N. L., Aboghaba, B., and Elrayess, M. A. (2021). The impact of acute and chronic exercise on immunoglobulins and cytokines in elderly: insights from a critical review of the literature. Front. Immunol. 12:631873.
Senatore, A., Restelli, E., and Chiesa, R. (2013). Synaptic dysfunction in prion diseases: a trafficking problem? Int. J. Cell Biol. 2013:543803.
Shah, S. Z. A., Zhao, D., Hussain, T., Sabir, N., Mangi, M. H., and Yang, L. (2018). p62-Keap1-NRF2-ARE pathway: a contentious player for selective targeting of autophagy, oxidative stress and mitochondrial dysfunction in prion diseases. Front. Mol. Neurosci. 11:310. doi: 10.3389/fnmol.2018.00310
Silveira, C. R. A., Roy, E. A., and Almeida, Q. J. (2018). Acute effects of aerobic exercise on cognitive function in individuals with Parkinson’s disease. Neurosci. Lett. 671, 60–65. doi: 10.1016/j.neulet.2018.01.056
Sindona, C., Schepici, G., Contestabile, V., Bramanti, P., and Mazzon, E. (2021). NOX2 activation in COVID-19: possible implications for neurodegenerative diseases. Medicina (Kaunas) 57:604. doi: 10.3390/medicina57060604
Siniscalchi, C., Di Palo, A., Russo, A., and Potenza, N. (2021). Human MicroRNAs interacting with SARS-CoV-2 RNA sequences: computational analysis and experimental target validation. Front. Genet. 12:678994. doi: 10.3389/fgene.2021.678994
Sita, G., Graziosi, A., Hrelia, P., and Morroni, F. (2021). NLRP3 and Infections: β-Amyloid in inflammasome beyond neurodegeneration. Int. J. Mol. Sci. 22:6984. doi: 10.3390/ijms22136984
Snell, K. D. M. (2017). The rise of living alone and loneliness in history. Soc. Hist. 42, 2–28. doi: 10.1080/03071022.2017.1256093
Song, L., Wells, E. A., and Robinson, A. S. (2021). Critical molecular and cellular contributors to tau pathology. Biomedicines 9:190. doi: 10.3390/biomedicines9020190
Soto, C., and Pritzkow, S. (2018). Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat. Neurosci. 21, 1332–1340. doi: 10.1038/s41593-018-0235-9
Spires, T. L., Grote, H. E., Varshney, N. K., Cordery, P. M., van Dellen, A., Blakemore, C., et al. (2004). Environmental enrichment rescues protein deficits in a mouse model of Huntington’s disease, indicating a possible disease mechanism. J. Neurosci. 24, 2270–2276. doi: 10.1523/jneurosci.1658-03.2004
Spuntarelli, V., Luciani, M., Bentivegna, E., Marini, V., Falangone, F., Conforti, G., et al. (2020). COVID-19: is it just a lung disease? A case-based review. SN Compr. Clin. Med. 1–6. [Epub ahead of print].
Stam, N. C., Nithianantharajah, J., Howard, M. L., Atkin, J. D., Cheema, S. S., and Hannan, A. J. (2008). Sex-specific behavioural effects of environmental enrichment in a transgenic mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci. 28, 717–723. doi: 10.1111/j.1460-9568.2008.06374.x
Stockwell, S., Trott, M., Tully, M., Shin, J., Barnett, Y., Butler, L., et al. (2021). Changes in physical activity and sedentary behaviours from before to during the COVID-19 pandemic lockdown: a systematic review. BMJ Open Sport Exerc. Med. 7:e000960. doi: 10.1136/bmjsem-2020-000960
Su, C. M., Wang, L., and Yoo, D. (2021). Activation of NF-κB and induction of proinflammatory cytokine expressions mediated by ORF7a protein of SARS-CoV-2. Sci. Rep. 11:13464.
Subhramanyam, C. S., Wang, C., Hu, Q., and Dheen, S. T. (2019). Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin. Cell Dev. Biol. 94, 112–120. doi: 10.1016/j.semcdb.2019.05.004
Sun, H., Liu, M., Sun, T., Chen, Y., Lan, Z., Lian, B., et al. (2019). Age-related changes in hippocampal AD pathology, actin remodeling proteins and spatial memory behavior of male APP/PS1 mice. Behav. Brain Res. 376:112182. doi: 10.1016/j.bbr.2019.112182
Sungnak, W., Huang, N., Bécavin, C., Berg, M., Queen, R., Litvinukova, M., et al. (2020). SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat. Med. 26, 681–687. doi: 10.1038/s41591-020-0868-6
Swain, O., Romano, S. K., Miryala, R., Tsai, J., Parikh, V., and Umanah, G. K. E. (2021). SARS-CoV-2 neuronal invasion and complications: potential mechanisms and therapeutic approaches. J. Neurosci. 41, 5338–5349. doi: 10.1523/jneurosci.3188-20.2021
Tangalos, E. G., and Petersen, R. C. (2018). Mild cognitive impairment in geriatrics. Clin. Geriatr. Med. 34, 563–589.
Thakur, K. T., Miller, E. H., Glendinning, M. D., Al-Dalahmah, O., Banu, M. A., Boehme, A. K., et al. (2021). COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain awab148. [Epub ahead of print].
Toniolo, S., Scarioni, M., Di Lorenzo, F., Hort, J., Georges, J., Tomic, S., et al. (2021b). Dementia and COVID-19, a bidirectional liaison: risk factors, biomarkers, and optimal health care. J. Alzheimers Dis. 82, 883–898. doi: 10.3233/jad-210335
Toniolo, S., Di Lorenzo, F., Scarioni, M., Frederiksen, K. S., and Nobili, F. (2021a). Is the frontal lobe the primary target of SARS-CoV-2? J. Alzheimers Dis. 81, 75–81. doi: 10.3233/jad-210008
Too, L. K., Hunt, N., and Simunovic, M. P. (2021). The role of inflammation and infection in age-related neurodegenerative diseases: lessons from bacterial meningitis applied to Alzheimer disease and age-related macular degeneration. Front. Cell. Neurosci. 15:635486. doi: 10.3389/fncel.2021.635486
Triviño, J. J., and von Bernhardi, R. (2021). The effect of aged microglia on synaptic impairment and its relevance in neurodegenerative diseases. Neurochem. Int. 144:104982. doi: 10.1016/j.neuint.2021.104982
Troyer, E. A., Kohn, J. N., and Hong, S. (2020). Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain Behav. Immun. 87, 34–39. doi: 10.1016/j.bbi.2020.04.027
van Dellen, A., Blakemore, C., Deacon, R., York, D., and Hannan, A. J. (2000). Delaying the onset of Huntington’s in mice. Nature 404, 721–722. doi: 10.1038/35008142
Verkhratsky, A., Ho, M. S., Vardjan, N., Zorec, R., and Parpura, V. (2019). General pathophysiology of astroglia. Adv. Exp. Med. Biol. 1175, 149–179. doi: 10.1007/978-981-13-9913-8_7
Villarreal, A., Vidos, C., Monteverde Busso, M., Cieri, M. B., and Ramos, A. J. (2021). Pathological neuroinflammatory conversion of reactive astrocytes is induced by microglia and involves chromatin remodeling. Front. Pharmacol. 12:689346.
Vincenti, J. E., Murphy, L., Grabert, K., McColl, B. W., Cancellotti, E., Freeman, T. C., et al. (2015). Defining the microglia response during the time course of chronic neurodegeneration. J. Virol. 90, 3003–3017. doi: 10.1128/jvi.02613-15
von Bohlen Und Halbach, O. (2021). The angiotensin converting enzyme 2 (ACE2) system in the brain: possible involvement in Neuro-Covid. Histol. Histopathol. 18356. [Epub ahead of print].
Walker, E., Ploubidis, G., and Fancourt, D. (2019). Social engagement and loneliness are differentially associated with neuro-immune markers in older age: time-varying associations from the English Longitudinal Study of Ageing. Brain Behav. Immun. 82, 224–229. doi: 10.1016/j.bbi.2019.08.189
Walker, L. C., and Jucker, M. (2015). Neurodegenerative diseases: expanding the prion concept. Annu. Rev. Neurosci. 38, 87–103. doi: 10.1146/annurev-neuro-071714-033828
Wang, F., Kream, R. M., and Stefano, G. B. (2020). Long-term respiratory and neurological sequelae of COVID-19. Med. Sci. Monit. 26:e928996.
Williams, A., Lawson, L., Perry, V. H., and Fraser, H. (1994). Characterization of the microglial response in murin e scrapie. Neuropathol. Appl. Neurobiol. 20, 47–55. doi: 10.1111/j.1365-2990.1994.tb00956.x
Wissler Gerdes, E. O., Zhu, Y., Weigand, B. M., Tripathi, U., Burns, T. C., Tchkonia, T., et al. (2020). Cellular senescence in aging and age-related diseases: implications for neurodegenerative diseases. Int. Rev. Neurobiol. 155, 203–234. doi: 10.1016/bs.irn.2020.03.019
Wong, S. Q., Kumar, A. V., Mills, J., and Lapierre, L. R. (2020). Autophagy in aging and longevity. Hum. Genet. 139, 277–290.
Wouk, J., Rechenchoski, D. Z., Rodrigues, B. C. D., Ribelato, E. V., and Faccin-Galhardi, L. C. (2021). Viral infections and their relationship to neurological disorders. Arch. Virol. 166, 733–753. doi: 10.1007/s00705-021-04959-6
Xu, L., He, D., and Bai, Y. (2016). Microglia-mediated inflammation and neurodegenerative disease. Mol. Neurobiol. 53, 6709–6715. doi: 10.1007/s12035-015-9593-4
Yachou, Y., El Idrissi, A., Belapasov, V., and Ait Benali, S. (2020). Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: understanding the neurological manifestations in COVID-19 patients. Neurol. Sci. 41, 2657–2669. doi: 10.1007/s10072-020-04575-3
Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., et al. (2021). Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature 595, 565–571. doi: 10.1038/s41586-021-03710-0
Yang, Y. H., and Zhu, J. (2019). Targeting miR-106-3p facilitates functional recovery via inactivating inflammatory microglia and interfering glial scar component deposition after neural injury. Eur. Rev. Med. Pharmacol. Sci. 23, 9000–9008.
Zamponi, E., Buratti, F., Cataldi, G., Caicedo, H. H., Song, Y., Jungbauer, L. M., et al. (2017). Prion protein inhibits fast axonal transport through a mechanism involving casein kinase 2. PLoS One 12:e0188340. doi: 10.1371/journal.pone.0188340
Zamponi, E., and Pigino, G. F. (2019). Protein misfolding, signaling abnormalities and altered fast axonal transport: implications for alzheimer and prion diseases. Front. Cell. Neurosci. 13:350.
Zhang, H., Penninger, J. M., Li, Y., Zhong, N., and Slutsky, A. S. (2020). Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 46, 586–590.
Zhou, J., Liu, C., Sun, Y., Huang, W., and Ye, K. (2021). Cognitive disorders associated with hospitalization of COVID-19: results from an observational cohort study. Brain Behav. Immun. 91, 383–392. doi: 10.1016/j.bbi.2020.10.019
Keywords: mouse prion disease, virus infection, exacerbated inflammatory response, prion-like neurodegenerative diseases, exercise, sedentary lifestyle, microglia hyperactivation, GFAP astrocytes reactivity
Citation: Leite AOF, Bento Torres Neto J, dos Reis RR, Sobral LL, de Souza ACP, Trévia N, de Oliveira RB, Lins NAA, Diniz DG, Diniz JAP, Vasconcelos PFC, Anthony DC, Brites D and Picanço Diniz CW (2021) Unwanted Exacerbation of the Immune Response in Neurodegenerative Disease: A Time to Review the Impact. Front. Cell. Neurosci. 15:749595. doi: 10.3389/fncel.2021.749595
Received: 29 July 2021; Accepted: 23 September 2021;
Published: 22 October 2021.
Edited by:
Rodolfo Thome, GlaxoSmithKline, United StatesReviewed by:
Parisa Gazerani, Oslo Metropolitan University, NorwayJanos Groh, University Hospital Würzburg, Germany
Copyright © 2021 Leite, Bento Torres Neto, dos Reis, Sobral, de Souza, Trévia, de Oliveira, Lins, Diniz, Diniz, Vasconcelos, Anthony, Brites and Picanço Diniz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Daniel Guerreiro Diniz, danielguerreirodiniz@gmail.com