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Review

Neuroinflammation in Dementia—Therapeutic Directions in a COVID-19 Pandemic Setting

1
Department of Psychiatry, Wroclaw Medical University, 50-367 Wroclaw, Poland
2
Department of Pathology, Wroclaw Medical University, 50-367 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: Dolores Viña
Cells 2022, 11(19), 2959; https://doi.org/10.3390/cells11192959
Received: 8 August 2022 / Revised: 16 September 2022 / Accepted: 20 September 2022 / Published: 22 September 2022

Abstract

Although dementia is a heterogenous group of diseases, inflammation has been shown to play a central role in all of them and provides a common link in their pathology. This review aims to highlight the importance of immune response in the most common types of dementia. We describe molecular aspects of pro-inflammatory signaling and sources of inflammatory activation in the human organism, including a novel infectious agent, SARS-CoV-2. The role of glial cells in neuroinflammation, as well as potential therapeutic approaches, are then discussed. Peripheral immune response and increased cytokine production, including an early surge in TNF and IL-1β concentrations activate glia, leading to aggravation of neuroinflammation and dysfunction of neurons during COVID-19. Lifestyle factors, such as diet, have a large impact on future cognitive outcomes and should be included as a crucial intervention in dementia prevention. While the use of NSAIDs is not recommended due to inconclusive results on their efficacy and risk of side effects, the studies focused on the use of TNF antagonists as the more specific target in neuroinflammation are still very limited. It is still unknown, to what degree neuroinflammation resulting from COVID-19 may affect neurodegenerative process and cognitive functioning in the long term with ongoing reports of chronic post-COVID complications.
Keywords: neuroinflammation; TNF; SARS-CoV-2; COVID-19; glial cells; TNF antagonists neuroinflammation; TNF; SARS-CoV-2; COVID-19; glial cells; TNF antagonists

1. Introduction

Although dementia is a heterogenous group of diseases, inflammation has been shown to play a central role in all of them and provides a common link in their pathology. This review aims to highlight the importance of immune response in the most common types of dementia, discuss essential mechanisms and sources of neuroinflammation and potential therapeutic strategies.
Prolonged activation of pro-inflammatory responses in Alzheimer’s disease (AD) alters function of glial cells and in turn, further accelerates neuroinflammation [1]. Subsequent synaptic dysfunction and loss of neurons are responsible for clinical symptoms of the disease. Additionally, factors such as insufficient sleep length and subsequent reduction in amyloid clearance via the glymphatic system lead to amyloid accumulation, while simultaneously aggravating systemic inflammatory response [2]. Inflammation in vascular dementia (VaD) contributes to the three-hit hypothesis, along with hypertension and hypoxia [3]. Vasculitis is responsible for restricted blood circulation in microvessels and leads to decreased oxygen supply and regional glial activation favoring neuroinflammation in the central nervous system (CNS) [4,5]. In the following cascade, blood vessels undergo remodeling, the blood-brain barrier (BBB) becomes more permeable and microthrombi cause regional hypoxia and neural death [3,4,6]. While neuroinflammation in frontotemporal dementia (FTD) is evident with both pro- and anti-inflammatory cytokines levels increased in the brain, the impact of the systemic inflammatory activation remains inconclusive [7]. However, some studies indicate that FTD is associated with autoimmune activation and more frequent comorbidities such as thyroid and rheumatoid diseases but also with elevated TNF concentrations [8,9] These observations reflect the need to account for peripheral immune response in understanding pathology of the disease [10]. Lewy bodies, α-synuclein aggregates present in neurons are a hallmark trait of Lewy body dementia (LBD) [11]. Microglial phagocytosis of α-synuclein aggregates leads to a release of pro-inflammatory cytokines, such as IL-6, contributing to increased iron sequestration in neurons and exacerbating neural death [12]. α-synuclein acts as an agonist of microglial Toll-like Receptor 2 (TLR-2) resulting in oxidative stress and production of TNF, IL-1 and IL-6 [13]. Addressing evidence from Parkinson’s disease studies, extracellular α-synuclein stimulates leucine rich repeat kinase 2 (LRRK2) expression in monocytes, favoring their infiltration of the brain parenchyma [14,15]. Additionally, α-synuclein oligomers induce release of calcium from astrocytes leading in turn to glutamatergic neurotoxicity and synapse loss [16].
As briefly discussed above, source and role of inflammation varies widely depending on specific dementia type. However, recent research highlights the role of peripheral cytokines and immune cells in the neurodegenerative processes [17,18,19]. Numerous comorbidities, which are considered to be risk factors of cognitive decline, are linked to dementia pathology via several mechanisms, among which, inflammation plays a significant role. While some studies detected a small association between inflammatory markers and global cognition in the elderly or function disability in dementia patients, life-long immune response could not be accounted for in any of those studies [20,21,22]. Hence, it is currently argued that the total impact of systemic life-long pro-inflammatory activation, such as occurs in obesity or rheumatoid diseases, and its role in cognitive decline require further exploration. In the following sections we describe molecular aspects of pro-inflammatory signaling and sources of inflammatory activation in the human organism, with a special regard to a novel infectious agent, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). The role of glial cells in neuroinflammation, as well as potential therapeutic approaches, are discussed.

2. Tumor Necrosis Factor Triggers Dementia Pathology

Among various cytokines involved in the immune response, tumor necrosis factor (TNF) is considered to play a significant upstream role in dementia pathology on a molecular level. Its pleiotropic effects vary from physiological neuroprotective and repair activities to pathological neuronal loss occurring in neurodegenerative and autoimmune conditions which are dependent on TNF form and activated receptor [23]. TNF receptor type 1 (TNFR1) is commonly expressed and can be bound by both transmembrane and soluble TNF forms, while TNF receptor type 2 (TNFR2), expressed by myeloid and endothelial cells but also by CNS-residing glia and neurons, is mainly bound by transmembrane TNF [24]. Protective versus deleterious outcomes of receptor activation depend on various factors including TNF concentration, activation of other signaling pathways or cell susceptibility resulting from cell type and age-related priming [25,26]. TNF signaling activates intracellular pathways with transcription factors such as NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) leading to pro-inflammatory cytokine production and, in conditions of prolonged signaling, aggravation of inflammation [27,28].
Exposure to TNF in an in vitro AD model has been shown to result in aggregation of extracellular proteins which are considered characteristic traits of AD and LBD pathology [29]. Interestingly, exposure to TNF does not need to be sustained in order to maintain increased secretion and aggregation of amyloid-β or α-synuclein in such models. This mechanism may demonstrate profound effects of TNF signaling on pro-inflammatory activation and cytokine production of astrocytes and microglia, leading to prolonged neuroinflammation [30]. This phenomenon has been reflected in a cohort study by Lindbergh et al., in which TNF plasma concentration of participants were assessed annually. Increased systemic TNF resulted in reduction in grey matter volumes in further assessments in a curvilinear correlation, with initially-increased TNF correlating with following loss of volume [31]. Additionally, within-person increases in TNF correlated with lower scores obtained in neuropsychological evaluation with the use of Mini Mental State Examination.

3. Mechanisms of Chronic Low-Grade Inflammation

Chronic low-grade inflammation stems from various conditions such as obesity, autoimmune and metabolic diseases, but also from psychosocial stressors. Adipokines released by white adipose tissue favor low-grade chronic inflammation and it has been shown that resulting changes to cytokine levels in mouse hippocampi can be elicited by simple fat tissue transplantation [32,33]. Obesity in humans is associated with greater neuroinflammation and worse cognitive performance, as shown by Samara et al., in a cohort study [34]. The impact of obesity on cognition is mediated both by adipokine dysfunction and increased production of pro-inflammatory cytokines by activated adipocytes [35,36]. Rheumatoid diseases are linked to a higher risk of atherosclerotic lesions and the proposed mediator is low-grade inflammation [37]. Both metabolic syndrome and type 2 diabetes have also been implicated in low-grade inflammation [38]. Moreover, in a longitudinal study chronic work-related stressors were associated with increased inflammatory index in men [39].
Another important factor in pro-inflammatory activation of the immune system seems to be composition of gut microbiota, which interestingly, has also been associated with above-mentioned causes of chronic inflammation [40]. Recent studies highlight the influence of diverse and complex environments present in the gastrointestinal tract on various health outcomes, including neurodegenerative diseases [41]. The bidirectional relations between gut microbiota and brain are reflected by the term gut-brain axis in which both blood and vagus nerve serve as mediators. In Parkinson’s disease α-synuclein aggregates are detected in intestinal submucosal plexus in a prodromal stage of disease [42]. Additionally, pathological α-synuclein was shown to be reversely transported via vagus nerve in animal models [43]. A similar mechanism has also been hypothesized for amyloid-β in AD [44]. The noteworthy mechanisms of microbial impact on the CNS include (1) intestinal production of cytokines; (2) entry of bacterial toxins, such as lipopolysaccharides, to the bloodstream; (3) microbial production of neurotransmitters; (4) direct passage of microbes to bloodstream and reactive production of cytokines by immune cells, but also (5) microbial entry to the CNS. Several highly adapted bacterial species, such as Streptococcus pneumoniae or Neisseria meningitidis are able to cross the BBB, often leading to its disruption and clinical manifestations of neurological infection. However, most of the microbial interactions with the CNS are considered to occur in a chronic, life-long fashion [45,46]. On the other hand, it is argued that activation of hypothalamic-pituitary-adrenal axis by circulating lipopolysaccharides constitutes CNS response and affects the gastrointestinal tract in a feedback loop manner [47].

4. SARS-CoV-2—A Novel Source of Neuroinflammation?

Recently, global exposure to the novel infectious agent, SARS-CoV-2, raises a question about neuroinflammatory consequences of COVID-19 (Coronavirus Disease 2019). Despite the fact that most cases of the infections are mild, their long-term effects in humans remain unknown [48]. SARS-CoV-2 has proven neurotropism and was shown to enter the CNS and disrupt the BBB integrity [49,50,51,52]. The entry of the virus to the CNS could occur via the olfactory nerve retrograde route but also with viral particles infecting endothelial cells and in conditions of BBB impairment, also pericytes and astrocytes [53,54].
So far, insufficient data exists on hypothesized retrograde axonal transport of the SARS-CoV-2. However, potential cellular mechanisms for this pathway could include ESCPE-1 retrograde trafficking. This endosomal transport system is responsible for sorting of neuropilin-1, which was shown to be a host factor for SARS-CoV-2 infection but further studies are required in order to confirm this pathway [55]. While evidence exists that virus present in the blood infects endothelial cells causing loss of the BBB integrity and allowing for entry to the CNS [56,57], it is still unclear whether disruption of BBB occurs due to tight junctions alterations [58] or basement membrane remodeling [59]. Another hypothesized pathway is the ‘Trojan horse’ mechanism observed in HIV infection, with infected circulating macrophages crossing the BBB and transporting SARS-CoV-2 to the brain compartment [60].
The apolipoprotein E4 (ApoE4) genotype has been associated with decreased antiviral defense gene expression resulting in increased risk of neuronal or astrocytic infection and more aggravated inflammatory response in astrocytes [61,62]. This finding links COVID-19 to AD pathology, for which ApoE4 gene is a well-established risk factor. Brain-residing cells, such as neurons, glia or pericytes have been shown to express the angiotensin-converting enzyme (ACE2) receptor, which facilitates viral infection in other organs such as lungs or heart [63,64,65]. Studies conducted in vitro indicate that SARS-CoV-2 infection in neurons results in synapse loss along with a decreased number and impaired morphology of neurites [61]. Furthermore, a multimodal omics approach revealed correlations between COVID-19 neuroinflammation and cognitive decline, with special emphasis on AD microvascular injury pathways [62].
While acute infection has been documented to cause neurological conditions such as encephalopathy and meningoencephalitis, their occurrence does not require the viral invasion of the CNS but can also result from other neuroinflammatory pathways [66]. In a study of 29 COVID-19 patients with neurological manifestations of the disease, most of them did not test positively for SARS-CoV-2 RNA in the cerebrospinal fluid (CSF) samples [67]. The total impact of the inflammatory activation in the CNS by SARS-CoV-2 is yet to be described. Peripheral immune response and increased cytokine production, including an early surge in TNF and IL-1β concentrations, impact the CNS-residing cells and favor their priming [53,54,66,68,69,70,71] (Figure 1). One of the proposed mechanisms of this phenomenon is entry of the peripheral pro-inflammatory signaling to the CNS via endothelial cells [72]. The effects of systemic inflammation observed in the brain compartment during COVID-19 have been described in several reports in which CSF pro-inflammatory cytokines levels were elevated throughout the course of the disease [73,74]. Additionally, cardiovascular consequences of COVID-19, such as coagulopathy and stroke, also contribute to cognitive decline [68,70,75]. As it turns out, despite some reports of viral presence in the CNS, the relevant consequences of COVID-19 in regard to neurodegeneration may actually occur without infiltration or replication of SARS-CoV-2 in the brain compartment. So far, a novel somatic symptomatology similar to chronic fatigue syndrome has been reported and described as post-COVID syndrome or long COVID [76], but other long-term consequences of COVID-19 may be reported in the future and more mechanistic studies are required in order to answer which pathways are of importance in their development.

5. Glial Involvement in Neuroinflammation

Research shows that the physiological neuroprotective immune response becomes impaired in conditions of prolonged pro-inflammatory activation in the CNS. The intricate interplay between different cell types residing in the CNS, such as neurons, microglia or astrocytes, becomes disturbed, eventually altering their function and leading to progressive aggravation of molecular pathology. Glial cells take part in nourishment of neurons but also affect their maturation, synapse formation and proper function [77,78]. It has been shown that both astrocytes and microglia exhibit neuroprotective and neuroinflammatory phenotypes, though these two main phenotypes may vary widely [79,80,81]. Loss of neuroprotective glial functions may in fact be associated with age-related decrease in acetylcholine receptors which are responsible for anti-inflammatory glial actions [80,82].
Astrocytes, the most numerous cells in the CNS maintain proper neurotransmission, regulate neural metabolism and oxidative status and contribute to glymphatic clearance of deleterious substrates [83,84]. Along with neurons and endothelial cells they allow for neurovascular coupling crucial for separation but also equilibrium maintenance in blood and brain compartments [85]. However, in neurodegenerative diseases their neuroprotective and neuroregulatory roles are impaired. Evidence indicates that astrocytes exhibit more pro-inflammatory phenotype with older age [86]. Exposure to phosphorylated tau oligomers evokes a pro-inflammatory astrocyte phenotype in AD and FTD patients resulting in a further increase in TNF production and activation of inflammatory phenotypes in surrounding cells [87]. Additionally, activated astrocytes are implicated in amyloid production increasing amyloid burden in the CNS, while their effectiveness in amyloid clearance decreases with time [79]. In LBD, α-synuclein aggregates accumulate in astrocytes leading to their chronic activation [83]. Microangiopathy impairs function of the neurovascular unit. In such conditions, astrocytes lose their buffering function leading to potassium imbalance and altered neuronal excitability [88]. In an animal model of VaD, reactive astrocytes significantly influenced survival of hypoxic neurons, which was mediated by lipocalin-2 expression [89]. Use of human-induced pluripotent stem cells and their differentiation into astrocytes led to remyelination and axonal sprouting enabling improvement of cognitive functions in another rodent model of VaD [90].
Microglia are primary immune cells responsible for phagocytosis, cytokine production and immune surveillance in the CNS [91,92]. However, their longevity and low turnover facilitate development of age-related neurodegenerative diseases [93]. It is currently believed that throughout life microglia respond to various stressors and become primed leading to often exaggerated and prolonged inflammatory responses to stimuli present in older age [94,95,96]. Primed microglia are characterized by less efficient amyloid phagocytosis and greater production of pro-inflammatory cytokines, such as TNF [97,98]. Interestingly, TNF has been shown to inhibit microglial clearance and increase production of amyloid in the CNS [99]. The primed microglia are also characterized with overexpression of immune surface protein TREM 2 (triggering receptor expressed on myeloid cells 2), which initially helps to alleviate amyloid burden [80,100]. In the brain compartment TREM2 is expressed by microglia only and promotes their survival, activation and phagocytosis [101,102]. CSF concentration of its soluble form, sTREM2, is indicative of neurodegeneration, with its higher levels correlating with slower cognitive decline in AD patients [103]. TREM gene variants have been implicated in pathologies of AD, FTD, along with α-synucleinopathies [101]. However, conflicting results from animal studies lead to the conclusion that the role of TREM2 in dementia pathology may actually be dependent on the stage of disease, with TREM2 reducing amyloidogenesis at early stages but eventually increasing development of amyloid plaques [104,105,106,107]. The reasons for the changed outcome of this signaling pathways may result from prolonged peripheral inflammatory activation influencing the CNS and therefore, activation of other signaling pathways.
Apparently, impaired microglial function resulting in ineffective amyloid plaque clearance favors development of microgliosis. In neurodegenerative diseases such as AD and LBD, the total number of microglia is increased, while number of activated microglia correlates with observed tau pathology [99,108]. Tau aggregates, have in turn been shown to induce NLRP3 inflammasome activation, leading to further production of IL-1β by microglia and aggravation of neuroinflammation [109]. Of note, pharmacological reduction in microgliosis and alteration of the glial pro-inflammatory phenotype leads to alleviation of tau-related pathology and improvement of cognitive functioning in an animal model [110]. Evidence exists, that activated glia may in fact facilitate propagation of α-synuclein pathology in in vitro models of α-synucleinopathies [111,112,113]. Additionally, microglia and astrocytes have been implicated in defective autophagy and glutamate excitotoxicity in FTD [114,115,116].

6. Methods for Reduction of Pro-Inflammatory Activation—Critical Appraisal

Since TNF signaling exerts a triggering effect in the development of cognitive decline [29,31], the question arises, whether interventions focused on reduction in TNF concentrations or inhibition of its signaling pathway may play a role in dementia prevention or treatment. There are several methods of reducing an inflammatory state in the human organism, including dietary and pharmacological interventions.
Diet has been implicated in pathology of numerous neurodegenerative diseases, including dementia. A well-balanced diet provides all nutritional ingredients necessary for maintaining healthy and functional neurons [117]. On the other hand, it is believed that diet largely impacts inflammatory activation and immune response, which in turn influences regional inflammatory response in the brain. Various studies, including large cohorts, have associated inflammatory dietary patterns with faster cognitive decline and subsequent cognitive impairment [118,119,120]. The correlation between inflammatory diet and cognition is especially apparent in regard to several cognitive functions, such as episodic memory, semantic-based memory, executive functions and working memory [121].
The Western diet which comprises highly-processed food rich in fructose and saturated fat is known to increase TNF concentration in animal models [122]. Mice immunized against Klebsiella pneumoniae were shown to have lower levels of inflammasome-related inflammation, providing yet another link between gut microbiota and inflammation. This phenomenon was mediated by the presence of apolipoprotein E and was not observed in ApoE −/− animals [122]. Although individually tailored diets are not yet within reach and require further exploration, some conclusions regarding the influence of particular diets on neurodegenerative processes can be made based on existing studies [123]. For example, use of Dietary Inflammatory index (DII), which takes into account individual’s dietary composition and characteristics, allows us to indicate the general influence of one’s diet on systemic cytokine levels and inflammatory activation [124]. Higher scores of DII were shown to strongly correlate with worse cognitive performance [125]. It stands to reason, that the influence of environmental factors such as diet in preserving cognition cannot be underestimated. On the other hand, it seems that the inflammatory potential of the consumed food may be related not only to the specific products but also to the gut microbiota composition resulting from the daily diet. A summary of findings associated with specific diets can be found in Table 1 [126,127,128,129,130,131,132,133,134,135].
Non-steroidal anti-inflammatory drugs (NSAIDs), the most commonly used anti-inflammatory drugs, were considered as potential dementia preventive agents in numerous studies. Some animal and human cohort studies suggested a beneficial influence of a daily intake of specific NSAIDs in preventing development or progression of most common types of dementia via reducing distinct dementia pathology [136,137,138]. However, large randomized clinical-trials or meta-analyses did not provide strong evidence supporting their recommended use, with a special regard to the dangerous side effects of their daily intake, such as potential gastrointestinal bleeding [139,140,141,142,143,144,145,146].
TNF antagonists offer yet another interesting approach to reducing inflammatory activation in humans. These agents are commonly used in autoimmune diseases, such as rheumatoid arthritis, psoriasis or inflammatory bowel diseases [147]. Their effects in controlling excessive immune response are mediated by binding TNF but the exact mechanisms and affinity to soluble and transmembrane TNF vary, hence their clinical use can also differ [26,148,149]. Moreover, some other mechanisms of action have been described, such as lymphotoxin-α blocking by etanercept. Additionally, infliximab has been proven to reduce expression of GM-CSF (granulocyte-macrophage colony stimulating factor) [150,151], while infliximab and adalimumab are able to induce production of immunosuppressive IL-10 by macrophages in vitro [152]. Psoriasis patients treated with etanercept had decreased expression of IL-1 and IL-8 genes which correlated with reduction in total pro-inflammatory immune response [153]. Importantly, although molecular weight and properties do not allow for free entry of TNF antagonists into the CNS, evidence indicates that these drugs may have protective influence against brain aging.
It seems that both BBB-nonpenetrating and modified, BBB-penetrating, etanercept reduce tauopathy, microgliosis and therefore, neuronal loss in a mouse model of AD. Additionally, they increase PSD95 protein levels indicating synaptic health. This phenomenon may be related to the peripheral effects of the drug and underlines the importance of tackling chronic inflammatory activation in order to maintain physiological neuronal function [154]. Similar observations had been made previously, in a study by Chang et al. [155]. Administration of BBB-penetrating TNF-inhibitor, cTfRMAb-TNFR, resulted in a significant decrease in neuroinflammatory markers, amyloid burden and BBB disruption in an AD mouse model. These results were comparable to those obtained with the use of etanercept in regard to amyloid burden and BBB integrity but not for neuroinflammation portrayed with ICAM-1 concentration. The cognitive performance of tested mice was highest in a group treated with cTfRMAb-TNFR highlighting the crucial role of neuroinflammation in cognitive decline [155]. Use of BBB-penetrating agents remains especially interesting in regard to FTD pathology, in which cytokine production seems to take place mainly in the brain [7].
An experiment conducted in an animal model of metabolic syndrome proved that intraperitoneal administration of infliximab improved lipid profiles in rats—i.e., decreased triglycerides and increased HDL. Additionally, the study group had lower adiponectin concentrations compared to the control, impacting low-grade inflammation. Noteworthy, not all metabolic aspects were normalized and cognitive tests were not included in the study protocol [156]. It may be hypothesized that an up-stream role of TNF in obesity-induced pathology, limits the potential protective effects of TNF inhibition in conditions of already present metabolic syndrome. On the other hand, intracerebroventricular administration of infliximab in a transgenic mouse model of AD resulted in a significant decrease in brain TNF levels, reduction in amyloid burden and tau pathology [157]. Another study conducted in a rat model of VaD, revealed a therapeutic effect of adalimumab administration in treating cognitive deficits resulting from cerebral hypoperfusion. This finding was associated with a reduction in neuronal loss and of microglial activation mediated by NFκB suppression [158].
A systematic literature review of TNF antagonist effects on AD revealed beneficial influence of TNF inhibition on cognition [27]. Most commonly studied agents, etanercept, infliximab and adalimumab, used in rheumatoid arthritis coincided with up to 60–70% reduction in AD incidence in large epidemiological analyzes of rheumatoid arthritis patients, whereas other methods of treatment did not affect AD incidence [159]. Similar results were obtained in patients with psoriasis who were treated with etanercept, infliximab or adalimumab [160]. Rheumatoid arthritis and psoriasis, among other autoimmune diseases, are known risk factors of AD due to the occurrence of persistent inflammatory activation which may constitute a confounding factor for generalized conclusions [161,162,163]. However, these observations warrant further research in other populations in order to establish a protective role of TNF inhibition on development and progression of various types of dementia. Updates on current clinical trials can be found in Table 2.

7. Conclusions

TNF, a key pro-inflammatory cytokine, plays a central role in the pathology of several types of dementia. Neuroinflammatory aspects of neurodegenerative diseases are related to various factors, both peripheral and located in the CNS. Pro-inflammatory cytokines prime glial cells, leading to aggravation of neuroinflammation. Unsurprisingly, lifestyle factors, such as diet, have a large impact on cognitive outcomes and should be considered as a crucial step in dementia prevention. So far, insufficient data exists on the use of TNF antagonists in dementia prevention and treatment. The predominance of studies conducted in AD models and the few experiments exploring their effects in other types of dementia may constitute a relevant research gap. Focused randomized clinical trials are warranted in order to establish the efficacy of anti-TNF agents and their mechanisms of action in most common types of dementia. It is still unknown, to what degree neuroinflammation resulting from COVID-19 may affect neurodegenerative processes and cognitive functioning in the long term with ongoing reports of chronic post-COVID complications. However, neuroinflammatory aspects of novel common infectious agents need to be taken into account in order to plan potential interventions focused on reduction in immune senescence in dementia treatment.

Author Contributions

Conceptualization, M.Ł. and J.R.; Investigation, M.Ł. and M.W.; Writing—Original Draft Preparation, M.Ł.; Writing—Review and Editing, M.W. and J.R.; Visualization, M.Ł.; Supervision, M.W. and J.R.; Funding Acquisition, M.Ł. and J.R. All authors have read and agreed to the published version of the manuscript.

Funding

The publication was prepared under the project financed from the funds granted by the Ministry of Education and Science in the “Regional Initiative of Excellence” program for the years 2019–2022, project number 016/RID/2018/19, the amount of funding 9 354 023,74 PLN.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ozben, T.; Ozben, S. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease. Clin. Biochem. 2019, 72, 87–89. [Google Scholar] [CrossRef] [PubMed]
  2. Irwin, M.R.; Vitiello, M.V. Implications of sleep disturbance and inflammation for Alzheimer’s disease dementia. Lancet Neurol. 2019, 18, 296–306. [Google Scholar] [CrossRef]
  3. Rosenberg, G.A. Extracellular matrix inflammation in vascular cognitive impairment and dementia. Clin. Sci. 2017, 131, 425–437. [Google Scholar] [CrossRef] [PubMed]
  4. Wang, X.X.; Zhang, B.; Xia, R.; Jia, Q.Y. Inflammation, apoptosis and autophagy as critical players in vascular dementia. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 9601–9614. [Google Scholar] [PubMed]
  5. Zhang, L.Y.; Pan, J.; Mamtilahun, M.; Zhu, Y.; Wang, L.; Venkatesh, A.; Shi, R.; Tu, X.; Jin, K.; Wang, Y.; et al. Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion. Theranostics 2020, 10, 74–90. [Google Scholar] [CrossRef] [PubMed]
  6. Frantellizzi, V.; Pani, A.; Ricci, M.; Locuratolo, N.; Fattapposta, F.; De Vincentis, G. Neuroimaging in Vascular Cognitive Impairment and Dementia: A Systematic Review. J. Alzheimer’s Dis. 2020, 73, 1279–1294. [Google Scholar] [CrossRef]
  7. Sjogren, M. Increased intrathecal inflammatory activity in frontotemporal dementia: Pathophysiological implications. J. Neurol. Neurosurg. Psychiatry 2004, 75, 1107–1111. [Google Scholar] [CrossRef]
  8. Miller, Z.A.; Rankin, K.P.; Graff-Radford, N.R.; Takada, L.T.; Sturm, V.E.; Cleveland, C.M.; Criswell, L.A.; Jaeger, P.A.; Stan, T.; Heggeli, K.A.; et al. TDP-43 frontotemporal lobar degeneration and autoimmune disease. J. Neurol. Neurosurg. Psychiatry 2013, 84, 956–962. [Google Scholar] [CrossRef]
  9. Miller, Z.A.; Sturm, V.E.; Camsari, G.B.; Karydas, A.; Yokoyama, J.S.; Grinberg, L.T.; Boxer, A.L.; Rosen, H.J.; Rankin, K.P.; Gorno-Tempini, M.L.; et al. Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts Completing the picture. Neurol. Neuroimmunol. Neuroinflamm. 2016, 3, e301. [Google Scholar] [CrossRef]
  10. McCauley, M.E.; Baloh, R.H. Inflammation in ALS/FTD pathogenesis. Acta Neuropathol. 2019, 137, 715–730. [Google Scholar] [CrossRef]
  11. Hallett, P.J.; Engelender, S.; Isacson, O. Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson’s disease. J. Neuroinflamm. 2019, 16, 153. [Google Scholar] [CrossRef] [PubMed]
  12. Lim, S.; Chun, Y.; Lee, J.S.; Lee, S.J. Neuroinflammation in Synucleinopathies. Brain Pathol. 2016, 26, 404–409. [Google Scholar] [CrossRef] [PubMed]
  13. Kim, C.; Ho, D.H.; Suk, J.-E.; You, S.; Michael, S.; Kang, J.; Joong Lee, S.; Masliah, E.; Hwang, D.; Lee, H.-J.; et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 2013, 4, 1562. [Google Scholar] [CrossRef] [PubMed]
  14. Ahmadi Rastegar, D.; Hughes, L.P.; Perera, G.; Keshiya, S.; Zhong, S.; Gao, J.; Halliday, G.M.; Schüle, B.; Dzamko, N. Effect of LRRK2 protein and activity on stimulated cytokines in human monocytes and macrophages. NPJ Parkinson’s Dis. 2022, 8, 34. [Google Scholar] [CrossRef]
  15. Xu, E.; Boddu, R.; Abdelmotilib, H.A.; Sokratian, A.; Kelly, K.; Liu, Z.; Bryant, N.; Chandra, S.; Carlisle, S.M.; Lefkowitz, E.J.; et al. Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain. Mol. Neurodegener. 2022, 17, 7. [Google Scholar] [CrossRef]
  16. Trudler, D.; Sanz-Blasco, S.; Eisele, Y.S.; Ghatak, S.; Bodhinathan, K.; Akhtar, M.W.; Lynch, W.P.; Piña-Crespo, J.C.; Talantova, M.; Kelly, J.W.; et al. α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss. J. Neurosci. 2021, 41, 2264–2273. [Google Scholar] [CrossRef]
  17. Cyprien, F.; Courtet, P.; Maller, J.; Meslin, C.; Ritchie, K.; Ancelin, M.-L.; Artero, S. Increased serum C-reactive protein and corpus callosum alterations in older adults. Aging Dis. 2019, 10, 463–469. [Google Scholar] [CrossRef]
  18. Si, S.; Li, J.; Tewara, M.A.; Xue, F. Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study. Front. Immunol. 2021, 12, 720876. [Google Scholar] [CrossRef]
  19. Tao, Q.; Ang, T.F.A.; DeCarli, C.; Auerbach, S.H.; Devine, S.; Stein, T.D.; Zhang, X.; Massaro, J.; Au, R.; Qiu, W.Q. Association of Chronic Low-grade Inflammation with Risk of Alzheimer Disease in ApoE4 Carriers. JAMA Netw. Open 2018, 1, e183597. [Google Scholar] [CrossRef]
  20. Fard, M.T.; Cribb, L.; Nolidin, K.; Savage, K.; Wesnes, K.; Stough, C. Is there a relationship between low-grade systemic inflammation and cognition in healthy people aged 60–75 years? Behav. Brain Res. 2020, 383, 112502. [Google Scholar] [CrossRef]
  21. Cervellati, C.; Trentini, A.; Bosi, C.; Valacchi, G.; Morieri, M.L.; Zurlo, A.; Brombo, G.; Passaro, A.; Zuliani, G. Low-grade systemic inflammation is associated with functional disability in elderly people affected by dementia. GeroScience 2018, 40, 61–69. [Google Scholar] [CrossRef] [PubMed]
  22. Janowitz, D.; Habes, M.; Toledo, J.B.; Hannemann, A.; Frenzel, S.; Terock, J.; Davatzikos, C.; Hoffmann, W.; Grabe, H.J. Inflammatory markers and imaging patterns of advanced brain aging in the general population. Brain Imaging Behav. 2020, 14, 1108–1117. [Google Scholar] [CrossRef] [PubMed]
  23. Probert, L. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience 2015, 302, 2–22. [Google Scholar] [CrossRef] [PubMed]
  24. Decourt, B.; Lahiri, D.K.; Sabbagh, M.N. Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease. Curr. Alzheimer Res. 2016, 14, 412–425. [Google Scholar] [CrossRef]
  25. Montgomery, S.L.; Bowers, W.J. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J. Neuroimmune Pharmacol. 2012, 7, 42–59. [Google Scholar] [CrossRef]
  26. Tracey, D.; Klareskog, L.; Sasso, E.H.; Salfeld, J.G.; Tak, P.P. Tumor necrosis factor antagonist mechanisms of action: A comprehensive review. Pharmacol. Ther. 2008, 117, 244–279. [Google Scholar] [CrossRef]
  27. Torres-Acosta, N.; O’Keefe, J.H.; O’Keefe, E.L.; Isaacson, R.; Small, G. The rapeutic Potential of TNF-α Inhibition for Alzheimer’s Disease Prevention. J. Alzheimer’s Dis. 2020, 78, 619–626. [Google Scholar] [CrossRef]
  28. Brás, J.P.; Bravo, J.; Freitas, J.; Barbosa, M.A.; Santos, S.G.; Summavielle, T.; Almeida, M.I. TNF-alpha-induced microglia activation requires miR-342: Impact on NF-kB signaling and neurotoxicity. Cell Death Dis. 2020, 11, 415. [Google Scholar] [CrossRef]
  29. Whiten, D.R.; Brownjohn, P.W.; Moore, S.; De, S.; Strano, A.; Zuo, Y.; Haneklaus, M.; Klenerman, D.; Livesey, F.J. Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer’s disease neurons. Brain Commun. 2020, 2, fcaa146. [Google Scholar] [CrossRef]
  30. Raffaele, S.; Lombardi, M.; Verderio, C.; Fumagalli, M. TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions. Cells 2020, 9, 2145. [Google Scholar] [CrossRef]
  31. Lindbergh, C.A.; Casaletto, K.B.; Staffaroni, A.M.; Elahi, F.; Walters, S.M.; You, M.; Neuhaus, J.; Contreras, W.R.; Wang, P.; Karydas, A.; et al. Systemic tumor necrosis factor-alpha trajectories relate to brain health in typically aging older adults. J. Gerontol Ser. A Biol. Sci. Med. Sci. 2020, 75, 1558–1565. [Google Scholar] [CrossRef] [PubMed]
  32. Olsthoorn, L.; Vreeken, D.; Kiliaan, A.J. Gut Microbiome, Inflammation, and Cerebrovascular Function: Link between Obesity and Cognition. Front. Neurosci. 2021, 15, 761456. [Google Scholar] [CrossRef] [PubMed]
  33. Erion, J.R.; Wosiski-Kuhn, M.; Dey, A.; Hao, S.; Davis, C.L.; Pollock, N.K.; Stranahan, A.M. Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J. Neurosci. 2014, 34, 2618–2631. [Google Scholar] [CrossRef] [PubMed]
  34. Samara, A.; Murphy, T.; Strain, J.; Rutlin, J.; Sun, P.; Neyman, O.; Sreevalsan, N.; Shimony, J.S.; Ances, B.M.; Song, S.-K.; et al. Neuroinflammation and White Matter Alterations in Obesity Assessed by Diffusion Basis Spectrum Imaging. Front. Hum. Neurosci. 2020, 13, 464. [Google Scholar] [CrossRef]
  35. Karczewski, J.; Zielińska, A.; Staszewski, R.; Eder, P.; Dobrowolska, A.; Souto, E.B. Obesity and the Brain. Int. J. Mol. Sci. 2022, 23, 6145. [Google Scholar] [CrossRef]
  36. Litwiniuk, A.; Bik, W.; Kalisz, M.; Baranowska-Bik, A. Inflammasome nlrp3 potentially links obesity-associated low-grade systemic inflammation and insulin resistance with alzheimer’s disease. Int. J. Mol. Sci. 2021, 22, 5603. [Google Scholar] [CrossRef]
  37. Jeppesen, J. Low-grade chronic inflammation and vascular damage in patients with rheumatoid arthritis: Don’t forget “metabolic inflammation”. J. Rheumatol. 2011, 38, 595–597. [Google Scholar] [CrossRef]
  38. Calle, M.C.; Fernandez, M.L. Inflammation and type 2 diabetes. Diabetes Metab. 2012, 38, 183–191. [Google Scholar] [CrossRef]
  39. Duchaine, C.S.; Brisson, C.; Talbot, D.; Gilbert-Ouimet, M.; Trudel, X.; Vézina, M.; Milot, A.; Diorio, C.; Ndjaboué, R.; Giguère, Y.; et al. Psychosocial stressors at work and inflammatory biomarkers: PROspective Quebec Study on Work and Health. Psychoneuroendocrinology 2021, 133, 105400. [Google Scholar] [CrossRef]
  40. Scheithauer, T.P.M.; Rampanelli, E.; Nieuwdorp, M.; Vallance, B.A.; Verchere, C.B.; van Raalte, D.H.; Herrema, H. Gut Microbiota as a Trigger for Metabolic Inflammation in Obesity and Type 2 Diabetes. Front. Immunol. 2020, 11, 571731. [Google Scholar] [CrossRef]
  41. Łuc, M.; Misiak, B.; Pawłowski, M.; Stańczykiewicz, B.; Zabłocka, A.; Szcześniak, D.; Pałęga, A.; Rymaszewska, J. Gut microbiota in dementia. Critical review of novel findings and their potential application. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2021, 104, 110039. [Google Scholar] [CrossRef] [PubMed]
  42. Liang, Y.; Cui, L.; Gao, J.; Zhu, M.; Zhang, Y.; Zhang, H.L. Gut Microbial Metabolites in Parkinson’s Disease: Implications of Mitochondrial Dysfunction in the Pathogenesis and Treatment. Mol. Neurobiol. 2021, 58, 3745–3758. [Google Scholar] [CrossRef] [PubMed]
  43. Kim, S.; Kwon, S.-H.; Kam, T.-I.; Panicker, N.; Karuppagounder, S.S.; Lee, S.; Lee, J.H.; Kim, W.R.; Kook, M.; Foss, C.A.; et al. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease. Neuron 2019, 103, 627–641.e7. [Google Scholar] [CrossRef] [PubMed]
  44. Giovannini, M.G.; Lana, D.; Traini, C.; Vannucchi, M.G. The microbiota–gut–brain axis and alzheimer disease. From dysbiosis to neurodegeneration: Focus on the central nervous system glial cells. J. Clin. Med. 2021, 10, 2358. [Google Scholar] [CrossRef] [PubMed]
  45. Al-Obaidi, M.M.J.; Desa, M.N.M. Mechanisms of Blood Brain Barrier Disruption by Different Types of Bacteria, and Bacterial–Host Interactions Facilitate the Bacterial Pathogen Invading the Brain. Cell Mol. Neurobiol. 2018, 38, 1349–1368. [Google Scholar] [CrossRef]
  46. Morais, L.H.; Schreiber, H.L.; Mazmanian, S.K. The gut microbiota–brain axis in behaviour and brain disorders. Nat. Rev. Microbiol. 2021, 19, 241–255. [Google Scholar] [CrossRef]
  47. Jang, S.H.; Woo, Y.S.; Lee, S.Y.; Bahk, W.M. The brain–gut–microbiome axis in psychiatry. Int. J. Mol. Sci. 2020, 21, 7122. [Google Scholar] [CrossRef]
  48. de Erausquin, G.A.; Snyder, H.; Carrillo, M.; Hosseini, A.A.; Brugha, T.S.; Seshadri, S. The chronic neuropsychiatric sequelae of COVID-19: The need for a prospective study of viral impact on brain functioning. Alzheimer’s Dement. 2021, 17, 1056–1065. [Google Scholar] [CrossRef]
  49. Jacob, F.; Pather, S.R.; Huang, W.K.; Zhang, F.; Wong, S.Z.H.; Zhou, H.; Cubitt, B.; Fan, W.; Chen, C.Z.; Xu, M.; et al. Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism Predominates in Choroid Plexus Epithelium. Cell Stem Cell 2020, 27, 937–950.e9. [Google Scholar] [CrossRef]
  50. Hu, J.; Jolkkonen, J.; Zhao, C. Neurotropism of SARS-CoV-2 and its neuropathological alterations: Similarities with other coronaviruses. Neurosci. Biobehav. Rev. 2020, 119, 184–193. [Google Scholar] [CrossRef]
  51. Buzhdygan, T.P.; DeOre, B.J.; Baldwin-Leclair, A.; Bullock, T.A.; McGary, H.M.; Khan, J.A.; Razmpour, R.; Hale, J.F.; Galie, P.A.; Potula, R.; et al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier. Neurobiol. Dis. 2020, 146, 105131. [Google Scholar] [CrossRef] [PubMed]
  52. Yachou, Y.; El Idrissi, A.; Belapasov, V.; Ait Benali, S. Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: Understanding the neurological manifestations in COVID-19 patients. Neurol. Sci. 2020, 41, 2657–2669. [Google Scholar] [CrossRef] [PubMed]
  53. Xu, Y.; Zhuang, Y.; Kang, L. A Review of Neurological Involvement in Patients with SARS-CoV-2 Infection. Med. Sci. Monit. 2021, 27, e932962. [Google Scholar] [CrossRef]
  54. Karnik, M.; Beeraka, N.M.; Uthaiah, C.A.; Nataraj, S.M.; Bettadapura, A.D.S.; Aliev, G.; Madhunapantula, S.V. A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development. Mol. Neurobiol. 2021, 58, 4535–4563. [Google Scholar] [CrossRef] [PubMed]
  55. Simonetti, B.; Daly, J.L.; Simón-Gracia, L.; Klein, K.; Weeratunga, S.; Antón-Plágaro, C.; Tobi, A.; Hodgson, L.; Lewis, P.A.; Heesom, K.J.; et al. ESCPE-1 mediates retrograde endosomal sorting of the SARS-CoV-2 host factor Neuropilin-1. Proc. Natl. Acad. Sci. USA 2022, 119, e2201980119. [Google Scholar] [CrossRef] [PubMed]
  56. Liu, F.; Han, K.; Blair, R.; Kenst, K.; Qin, Z.; Upcin, B.; Wörsdörfer, P.; Midkiff, C.C.; Mudd, J.; Belyaeva, E.; et al. SARS-CoV-2 Infects Endothelial Cells In Vivo and In Vitro. Front. Cell. Infect. Microbiol. 2021, 11, 701278. [Google Scholar] [CrossRef]
  57. Krasemann, S.; Haferkamp, U.; Pfefferle, S.; Woo, M.S.; Heinrich, F.; Schweizer, M.; Appelt-Menzel, A.; Cubukova, A.; Barenberg, J.; Leu, J.; et al. The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Rep. 2022, 17, 307–320. [Google Scholar] [CrossRef]
  58. Yang, R.-C.; Huang, K.; Zhang, H.-P.; Li, L.; Zhang, Y.-F.; Tan, C.; Chen, H.-C.; Jin, M.-L.; Wang, X.-R. SARS-CoV-2 productively infects human brain microvascular endothelial cells. J. Neuroinflamm. 2022, 19, 149. [Google Scholar] [CrossRef]
  59. Zhang, L.; Zhou, L.; Bao, L.; Liu, J.; Zhu, H.; Lv, Q.; Liu, R.; Chen, W.; Tong, W.; Wei, Q.; et al. SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration. Signal Transduct. Target Ther. 2021, 6, 337. [Google Scholar]
  60. Huang, J.; Zheng, M.; Tang, X.; Chen, Y.; Tong, A.; Zhou, L. Potential of SARS-CoV-2 to Cause CNS Infection: Biologic Fundamental and Clinical Experience. Front. Neurol. 2020, 11, 659. [Google Scholar] [CrossRef]
  61. Wang, C.; Zhang, M.; Garcia, G.; Tian, E.; Cui, Q.; Chen, X.; Sun, G.; Wang, J.; Arumugaswami, V.; Shi, Y. ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response. Cell Stem Cell 2021, 28, 331–342.e5. [Google Scholar] [CrossRef] [PubMed]
  62. Zhou, Y.; Xu, J.; Hou, Y.; Leverenz, J.B.; Kallianpur, A.; Mehra, R.; Liu, Y.; Yu, H.; Pieper, A.A.; Jehi, L.; et al. Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimer’s Res. Ther. 2021, 13, 110. [Google Scholar] [CrossRef] [PubMed]
  63. Hernández, V.S.; Zetter, M.A.; Guerra, E.C.; Hernández-Araiza, I.; Karuzin, N.; Hernández-Pérez, O.R.; Eiden, L.E.; Zhang, L. ACE2 expression in rat brain: Implications for COVID-19 associated neurological manifestations. Exp. Neurol. 2021, 345, 113837. [Google Scholar] [CrossRef]
  64. Zhang, Y.; Archie, S.R.; Ghanwatkar, Y.; Sharma, S.; Nozohouri, S.; Burks, E.; Mdzinarishvili, A.; Liu, Z.; Abbruscato, T.J. Potential role of astrocyte angiotensin converting enzyme 2 in the neural transmission of COVID-19 and a neuroinflammatory state induced by smoking and vaping. Fluids Barriers CNS 2022, 19, 46. [Google Scholar] [CrossRef] [PubMed]
  65. Baig, A.M.; Khaleeq, A.; Ali, U.; Syeda, H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem. Neurosci. 2020, 11, 995–998. [Google Scholar] [CrossRef] [PubMed]
  66. Pallanti, S.; Grassi, E.; Makris, N.; Gasic, G.P.; Hollander, E. Neurocovid-19: A clinical neuroscience-based approach to reduce SARS-CoV-2 related mental health sequelae. J. Psychiatr. Res. 2020, 130, 215–217. [Google Scholar] [CrossRef] [PubMed]
  67. Paterson, R.W.; Brown, R.L.; Benjamin, L.; Nortley, R.; Wiethoff, S.; Bharucha, T.; Jayaseelan, D.L.; Kumar, G.; Raftopoulos, R.E.; Zambreanu, L.; et al. The emerging spectrum of COVID-19 neurology: Clinical, radiological and laboratory findings. Brain 2020, 143, 3104–3120. [Google Scholar]
  68. Bhaskar, S.; Sinha, A.; Banach, M.; Mittoo, S.; Weissert, R.; Kass, J.S.; Rajagopal, S.; Pai, A.R.; Kutty, S. Cytokine Storm in COVID-19—Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper. Front. Immunol. 2020, 11, 1648. [Google Scholar] [CrossRef]
  69. Gasmi, A.; Tippairote, T.; Mujawdiya, P.K.; Gasmi Benahmed, A.; Menzel, A.; Dadar, M.; Bjørklund, G. Neurological Involvements of SARS-CoV2 Infection. Mol. Neurobiol. 2021, 58, 944–949. [Google Scholar]
  70. Jarrahi, A.; Ahluwalia, M.; Khodadadi, H.; Da Silva Lopes Salles, E.; Kolhe, R.; Hess, D.C.; Vale, F.; Kumar, M.; Baban, B.; Vaibhav, K.; et al. Neurological consequences of COVID-19: What have we learned and where do we go from here? J. Neuroinflamm. 2020, 17, 286. [Google Scholar] [CrossRef]
  71. Tizenberg, B.N.; Brenner, L.A.; Lowry, C.A.; Okusaga, O.O.; Benavides, D.R.; Hoisington, A.J.; Benros, M.E.; Stiller, J.W.; Kessler, R.C.; Postolache, T.T. Biological and Psychological Factors Determining Neuropsychiatric Outcomes in COVID-19. Curr. Psychiatry Rep. 2021, 23, 68. [Google Scholar] [CrossRef] [PubMed]
  72. Murta, V.; Villarreal, A.; Ramos, A.J. Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders? ASN Neuro 2020, 12, 1759091420954960. [Google Scholar] [CrossRef] [PubMed]
  73. Muccioli, L.; Pensato, U.; Cani, I.; Guarino, M.; Cortelli, P.; Bisulli, F. COVID-19–Associated Encephalopathy and Cytokine-Mediated Neuroinflammation. Ann. Neurol. 2020, 88, 860–861. [Google Scholar] [CrossRef]
  74. Pilotto, A.; Padovani, A. Reply to the Letter “COVID-19-Associated Encephalopathy and Cytokine-Mediated Neuroinflammation”. Ann. Neurol. 2020, 88, 861–862. [Google Scholar] [CrossRef]
  75. Connors, J.M.; Levy, J.H. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020, 135, 2033–2040. [Google Scholar] [CrossRef]
  76. Tirelli, U.; Taibi, R.; Chirumbolo, S. Post COVID syndrome: A new challenge for medicine. Eur. Rev. Med. Pharmacol. Sci. 2021, 25, 4422–4425. [Google Scholar] [CrossRef]
  77. Stevenson, R.; Samokhina, E.; Rossetti, I.; Morley, J.W.; Buskila, Y. Neuromodulation of Glial Function During Neurodegeneration. Front. Cell. Neurosci. 2020, 14, 278. [Google Scholar] [CrossRef]
  78. Ferrer, I. Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner. Prog. Neurobiol. 2018, 169, 24–54. [Google Scholar] [CrossRef]
  79. Acioglu, C.; Li, L.; Elkabes, S. Contribution of astrocytes to neuropathology of neurodegenerative diseases. Brain Res. 2021, 1758, 147291. [Google Scholar] [CrossRef]
  80. Gamage, R.; Wagnon, I.; Rossetti, I.; Childs, R.; Niedermayer, G.; Chesworth, R.; Gyengesi, E. Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation. Front. Cell. Neurosci. 2020, 14, 577912. [Google Scholar] [CrossRef]
  81. Zhou, Y.; Song, W.M.; Andhey, P.S.; Swain, A.; Levy, T.; Miller, K.R.; Poliani, P.L.; Cominelli, M.; Grover, S.; Gilfillan, S.; et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med. 2020, 26, 131–142. [Google Scholar] [CrossRef] [PubMed]
  82. Court, J.A.; Lloyd, S.; Johnson, M.; Griffiths, M.; Birdsall, N.J.M.; Piggott, M.A.; Oakley, A.; Ince, P.; Perry, E.; Perry, R. Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation during development and aging. Dev. Brain Res. 1997, 101, 93–105. [Google Scholar] [CrossRef]
  83. Sorrentino, Z.A.; Giasson, B.I.; Chakrabarty, P. α-Synuclein and astrocytes: Tracing the pathways from homeostasis to neurodegeneration in Lewy body disease. Acta Neuropathol. 2019, 138, 1–21. [Google Scholar] [CrossRef]
  84. Radford, R.A.; Morsch, M.; Rayner, S.L.; Cole, N.J.; Pountney, D.L.; Chung, R.S. The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia. Front. Cell. Neurosci. 2015, 9, 414. [Google Scholar] [CrossRef] [PubMed]
  85. Iadecola, C. The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease. Neuron 2017, 96, 17–42. [Google Scholar] [CrossRef]
  86. Porchet, R.; Probst, A.; Bouras, C.; Dráberová, E.; Dráber, P.; Riederer, B.M. Analysis of gial acidic fibrillary protein in the human entorhinal cortex during aging and in Alzheimer’s disease. Proteomics 2003, 3, 1476–1485. [Google Scholar] [CrossRef]
  87. Gaikwad, S.; Puangmalai, N.; Bittar, A.; Montalbano, M.; Garcia, S.; McAllen, S.; Bhatt, N.; Sonawane, M.; Sengupta, U.; Kayed, R. Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia. Cell Rep. 2021, 36, 109419. [Google Scholar] [CrossRef]
  88. Price, B.R.; Norris, C.M.; Sompol, P.; Wilcock, D.M. An emerging role of astrocytes in vascular contributions to cognitive impairment and dementia. J. Neurochem. 2018, 144, 644–650. [Google Scholar] [CrossRef]
  89. Kim, J.H.; Ko, P.W.; Lee, H.W.; Jeong, J.Y.; Lee, M.G.; Kim, J.H.; Lee, W.-H.; Yu, R.; Oh, W.-J.; Suk, K. Astrocyte-derived lipocalin-2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia. Glia 2017, 65, 1471–1490. [Google Scholar] [CrossRef]
  90. Llorente, I.L.; Xie, Y.; Mazzitelli, J.A.; Hatanaka, E.A.; Cinkornpumin, J.; Miller, D.R.; Lin, Y.; Lowry, W.E.; Carmichael, S.T. Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents. Sci. Transl. Med. 2021, 13, eaaz6747. [Google Scholar] [CrossRef]
  91. DiSabato, D.J.; Quan, N.; Godbout, J.P. Neuroinflammation: The devil is in the details. J. Neurochem. 2016, 139, 136–153. [Google Scholar] [CrossRef] [PubMed]
  92. López-Valdés, H.E.; Martínez-Coria, H. The Role of Neuroinflammation in Age-Related Dementias. Rev. Investig. Clin. 2016, 68, 40–48. [Google Scholar]
  93. Ginhoux, F.; Greter, M.; Leboeuf, M.; Nandi, S.; See, P.; Gokhan, S.; Mehler, M.F.; Conway, S.J.; Ng, L.G.; Stanley, E.R.; et al. Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages. Science 2010, 330, 841–845. [Google Scholar] [CrossRef] [PubMed]
  94. Niraula, A.; Sheridan, J.F.; Godbout, J.P. Microglia Priming with Aging and Stress. Neuropsychopharmacology 2017, 42, 318–333. [Google Scholar] [CrossRef] [PubMed]
  95. Norden, D.M.; Godbout, J.P. Review: Microglia of the aged brain: Primed to be activated and resistant to regulation. Neuropathol. Appl. Neurobiol. 2013, 39, 19–34. [Google Scholar] [CrossRef]
  96. Wynne, A.M.; Henry, C.J.; Huang, Y.; Cleland, A.; Godbout, J.P. Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav. Immun. 2010, 24, 1190–1201. [Google Scholar] [CrossRef]
  97. Njie Malick, G.; Boelen, E.; Stassen, F.R.; Steinbusch, H.W.M.; Borchelt, D.R.; Streit, W.J. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol. Aging 2012, 33, 195.e1–195.e12. [Google Scholar] [CrossRef]
  98. Lee, S.; Varvel, N.H.; Konerth, M.E.; Xu, G.; Cardona, A.E.; Ransohoff, R.M.; Lamb, B.T. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am. J. Pathol. 2010, 177, 2549–2562. [Google Scholar] [CrossRef]
  99. Hampel, H.; Caraci, F.; Cuello, A.C.; Caruso, G.; Nisticò, R.; Corbo, M.; Baldacci, F.; Toschi, N.; Garaci, F.; Chiesa, P.A.; et al. A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer’s Disease. Front. Immunol. 2020, 11, 456. [Google Scholar] [CrossRef]
  100. Lee, C.Y.D.; Daggett, A.; Gu, X.; Jiang, L.L.; Langfelder, P.; Li, X.; Wang, N.; Zhao, Y.; Park, C.S.; Cooper, Y.; et al. Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models. Neuron 2018, 97, 1032–1048.e5. [Google Scholar] [CrossRef]
  101. Yeh, F.L.; Hansen, D.V.; Sheng, M. TREM2, Microglia, and Neurodegenerative Diseases. Trends Mol. Med. 2017, 23, 512–533. [Google Scholar] [CrossRef] [PubMed]
  102. Deczkowska, A.; Weiner, A.; Amit, I. The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway. Cell 2020, 181, 1207–1217. [Google Scholar] [CrossRef] [PubMed]
  103. Ewers, M.; Franzmeier, N.; Suárez-Calvet, M.; Morenas-Rodriguez, E.; Caballero, M.A.A.; Kleinberger, G.; Piccio, L.; Cruchaga, C.; Deming, Y.; Dichgans, M.; et al. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Sci. Transl. Med. 2019, 11, eaav6221. [Google Scholar] [CrossRef] [PubMed]
  104. Jay, T.R.; Hirsch, A.M.; Broihier, M.L.; Miller, C.M.; Neilson, L.E.; Ransohoff, R.M.; Lamb, B.T.; Landreth, G.E. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 2017, 37, 637–647. [Google Scholar] [CrossRef] [PubMed]
  105. Leyns, C.E.G.; Ulrich, J.D.; Finn, M.B.; Stewart, F.R.; Koscal, L.J.; Serrano, J.R.; Robinson, G.O.; Anderson, E.; Colonna, M.; Holtzman, D.M. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl. Acad. Sci. USA 2017, 114, 11524–11529. [Google Scholar] [CrossRef]
  106. Parhizkar, S.; Arzberger, T.; Brendel, M.; Kleinberger, G.; Deussing, M.; Focke, C.; Nuscher, B.; Xiong, M.; Ghasemigharagoz, A.; Katzmarski, N.; et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 2019, 22, 191–204. [Google Scholar] [CrossRef]
  107. Li, C.; Zhao, B.; Lin, C.; Gong, Z.; An, X. TREM2 inhibits inflammatory responses in mouse microglia by suppressing the PI3K/NF-κB signaling. Cell Biol. Int. 2019, 43, 360–372. [Google Scholar] [CrossRef]
  108. Carmona-Abellan, M.; Martinez-Valbuena, I.; Marcilla, I.; DiCaudo, C.; Gil, I.; Nuñez, J.; Luquin, M.-R. Microglia is associated with p-Tau aggregates in the olfactory bulb of patients with neurodegenerative diseases. Neurol. Sci. 2021, 42, 1473–1482. [Google Scholar] [CrossRef]
  109. Stancu, I.C.; Cremers, N.; Vanrusselt, H.; Couturier, J.; Vanoosthuyse, A.; Kessels, S.; Lodder, C.; Brône, B.; Huaux, F.; Octave, J.-N.; et al. Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019, 137, 599–617. [Google Scholar] [CrossRef]
  110. Mancuso, R.; Fryatt, G.; Cleal, M.; Obst, J.; Pipi, E.; Monzón-Sandoval, J.; Ribe, E.; Winchester, L.; Webber, C.; Nevado, A.; et al. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain 2019, 142, 3243–3264. [Google Scholar] [CrossRef]
  111. Radford, R.; Rcom-H’cheo-Gauthier, A.; Wong, M.B.; Eaton, E.D.; Quilty, M.; Blizzard, C.; Norazit, A.; Meedeniya, A.; Vickers, J.; Gai, W.P.; et al. The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to α-synuclein inclusions. Mol. Cell. Neurosci. 2015, 65, 68–81. [Google Scholar] [CrossRef] [PubMed]
  112. Valdinocci, D.; Radford, R.A.W.; Siow, S.M.; Chung, R.S.; Pountney, D.L. Potential modes of intercellular α-synuclein transmission. Int. J. Mol. Sci. 2017, 18, 469. [Google Scholar] [CrossRef] [PubMed]
  113. Hartnell, I.J.; Blum, D.; Nicoll, J.A.R.; Dorothee, G.; Boche, D. Glial cells and adaptive immunity in frontotemporal dementia with tau pathology. Brain 2021, 144, 724–745. [Google Scholar] [CrossRef] [PubMed]
  114. Strohm, L.; Behrends, C. Glia-specific autophagy dysfunction in ALS. Semin. Cell Dev. Biol. 2020, 99, 172–182. [Google Scholar] [CrossRef] [PubMed]
  115. Chandrasekaran, A.; Dittlau, K.S.; Corsi, G.I.; Haukedal, H.; Doncheva, N.T.; Ramakrishna, S.; Ambardar, S.; Salcedo, C.; Schmidt, S.I.; Zhang, Y.; et al. Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3. Stem Cell Rep. 2021, 16, 2736–2751. [Google Scholar] [CrossRef]
  116. Ghasemi, M.; Keyhanian, K.; Douthwright, C. Glial cell dysfunction in c9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia. Cells 2021, 10, 249. [Google Scholar] [CrossRef]
  117. Vasefi, M.; Hudson, M.; Ghaboolian-Zare, E. Diet Associated with Inflammation and Alzheimer’s Disease. J. Alzheimer’s Dis. Rep. 2019, 3, 299–309. [Google Scholar] [CrossRef]
  118. Ozawa, M.; Shipley, M.; Kivimaki, M.; Singh-Manoux, A.; Brunner, E.J. Dietary pattern, inflammation and cognitive decline: The Whitehall II prospective cohort study. Clin. Nutr. 2017, 36, 506–512. [Google Scholar] [CrossRef]
  119. Shin, D.; Kwon, S.C.; Kim, M.H.; Lee, K.W.; Choi, S.Y.; Shivappa, N.; Hébert, J.R.; Chung, H.-K. Inflammatory potential of diet is associated with cognitive function in an older adult Korean population. Nutrition 2018, 55–56, 56–62. [Google Scholar] [CrossRef]
  120. Hayden, K.M.; Beavers, D.P.; Steck, S.E.; Hebert, J.R.; Tabung, F.K.; Shivappa, N.; Casanova, R.; Manson, J.E.; Padula, C.B.; Salmoirago-Blotcher, E.; et al. The association between an inflammatory diet and global cognitive function and incident dementia in older women: The Women’s Health Initiative Memory Study. Alzheimer’s Dement. 2017, 13, 1187–1196. [Google Scholar] [CrossRef]
  121. Frith, E.; Shivappa, N.; Mann, J.R.; Hébert, J.R.; Wirth, M.D.; Loprinzi, P.D. Dietary inflammatory index and memory function: Population-based national sample of elderly Americans. Br. J. Nutr. 2018, 119, 552–558. [Google Scholar] [CrossRef]
  122. Saita, D.; Ferrarese, R.; Foglieni, C.; Esposito, A.; Canu, T.; Perani, L.; Ceresola, E.R.; Visconti, L.; Burioni, R.; Clementi, M.; et al. Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation. Sci. Rep. 2016, 6, 29353. [Google Scholar] [CrossRef] [PubMed]
  123. Milošević, M.; Arsić, A.; Cvetković, Z.; Vučić, V. Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition. Front. Nutr. 2021, 8, 688086. [Google Scholar] [CrossRef] [PubMed]
  124. Shivappa, N.; Steck, S.E.; Hurley, T.G.; Hussey, J.R.H.J. Dietary Inflammatory Index. Public Health Nutr. 2014, 17, 1689–1696. [Google Scholar] [CrossRef] [PubMed]
  125. Kesse-Guyot, E.; Assmann, K.E.; Andreeva, V.A.; Touvier, M.; Neufcourt, L.; Shivappa, N.; Hébert, J.R.; Wirth, M.D.; Hercberg, S.; Galan, P.; et al. Long-term association between the dietary inflammatory index and cognitive functioning: Findings from the SU.VI.MAX study. Eur. J. Nutr. 2017, 56, 1647–1655. [Google Scholar] [CrossRef]
  126. Ostan, R.; Béné, M.C.; Spazzafumo, L.; Pinto, A.; Donini, L.M.; Pryen, F.; Charrouf, Z.; Valentini, L.; Lochs, H.; Bourdel-Marchasson, I.; et al. Impact of diet and nutraceutical supplementation on inflammation in elderly people. Results from the RISTOMED study, an open-label randomized control trial. Clin. Nutr. 2016, 35, 812–818. [Google Scholar] [CrossRef]
  127. Kim, E.R.; Kim, S.R.; Cho, W.; Lee, S.G.; Kim, S.H.; Kim, J.H.; Choi, E.; Kim, J.-H.; Yu, J.-W.; Lee, B.-W.; et al. Short Term Isocaloric Ketogenic Diet Modulates NLRP3 Inflammasome Via B-hydroxybutyrate and Fibroblast Growth Factor 21. Front. Immunol. 2022, 13, 843520. [Google Scholar] [CrossRef]
  128. Al-Aubaidy, H.A.; Dayan, A.; Deseo, M.A.; Itsiopoulos, C.; Jamil, D.; Hadi, N.R.; Thomas, C. Twelve-week mediterranean diet intervention increases citrus bioflavonoid levels and reduces inflammation in people with type 2 diabetes mellitus. Nutrients 2021, 13, 1133. [Google Scholar] [CrossRef]
  129. Georgoulis, M.; Yiannakouris, N.; Tenta, R.; Fragopoulou, E.; Kechribari, I.; Lamprou, K.; Perraki, E.; Vagiakis, E.; Kontogianni, M.D. A weight-loss Mediterranean diet/lifestyle intervention ameliorates inflammation and oxidative stress in patients with obstructive sleep apnea: Results of the “MIMOSA” randomized clinical trial. Eur. J. Nutr. 2021, 60, 3799–3810. [Google Scholar] [CrossRef]
  130. Ojo, O.; Ojo, O.O.; Zand, N.; Wang, X. The Effect of Dietary Fibre on Gut Microbiota, Lipid Profile, and Inflammatory Markers in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Nutrients 2021, 13, 1805. [Google Scholar] [CrossRef]
  131. Shivappa, N.; Hebert, J.R.; Marcos, A.; Diaz, L.E.; Gomez, S.; Nova, E.; Michels, N.; Arouca, A.; González-Gil, E.; Frederic, G.; et al. Association between dietary inflammatory index and inflammatory markers in the HELENA study. Mol. Nutr. Food Res. 2017, 61, 1–23. [Google Scholar] [CrossRef]
  132. Casas, R.; Urpi-Sardà, M.; Sacanella, E.; Arranz, S.; Corella, D.; Castañer, O.; Lamuela-Raventós, R.-M.; Salas-Salvadó, J.; Lapetra, J.; Portillo, M.P.; et al. Anti-Inflammatory Effects of the Mediterranean Diet in the Early and Late Stages of Atheroma Plaque Development. Mediat. Inflamm. 2017, 2017, 3674390. [Google Scholar] [CrossRef] [PubMed]
  133. Mazzoli, A.; Spagnuolo, M.S.; Gatto, C.; Nazzaro, M.; Cancelliere, R.; Crescenzo, R.; Iossa, S.; Cigliano, L. Adipose tissue and brain metabolic responses to western diet—is there a similarity between the two? Int. J. Mol. Sci. 2020, 21, 786. [Google Scholar] [CrossRef]
  134. Jena, P.K.; Sheng, L.; Nguyen, M.; Di Lucente, J.; Hu, Y.; Li, Y.; Maezawa, I.; Jin, L.-W.; Wan, Y.-J.Y. Dysregulated bile acid receptor-mediated signaling and IL-17A induction are implicated in diet-associated hepatic health and cognitive function. Biomark. Res. 2020, 8, 59. [Google Scholar] [CrossRef]
  135. Godfrey, J.R.; Pincus, M.; Kovacs-Balint, Z.; Feczko, E.; Earl, E.; Miranda-Dominguez, O.; Fair, D.A.; Jones, S.R.; Locke, J.; Sanchez, M.M.; et al. Obesogenic diet-associated C-reactive protein predicts reduced central dopamine and corticostriatal functional connectivity in female rhesus monkeys. Brain Behav. Immun. 2020, 88, 166–173. [Google Scholar] [CrossRef]
  136. Weng, J.; Zhao, G.; Weng, L.; Guan, J. Aspirin using was associated with slower cognitive decline in patients with Alzheimer’s disease. PLoS ONE 2021, 16, e0252969. [Google Scholar] [CrossRef]
  137. Sekiyama, K.; Fujita, M.; Sekigawa, A.; Takamatsu, Y.; Waragai, M.; Takenouchi, T.; Sugama, S.; Hashimoto, M. Ibuprofen ameliorates protein aggregation and astrocytic gliosis, but not cognitive dysfunction, in a transgenic mouse expressing dementia with Lewy bodies-linked P123H β-synuclein. Neurosci. Lett. 2012, 515, 97–101. [Google Scholar] [CrossRef]
  138. Szekely, C.A.; Breitner, J.C.S.; Fitzpatrick, A.L.; Rea, T.D.; Psaty, B.M.; Kuller, L.H.; Zandi, P.P. NSAID use and dementia risk in the Cardiovascular Health Study: Role of APOE and NSAID type. Neurology 2008, 70, 17–24. [Google Scholar] [CrossRef]
  139. Knopman, D.S.; Petersen, R.C. The quest for dementia prevention does not include an aspirin a day. Neurology 2020, 95, 105–106. [Google Scholar] [CrossRef]
  140. Tabet, N.; Feldman, H. Ibuprofen for Alzheimer’s disease. Cochrane Database Syst. Rev. 2003, CD004031. [Google Scholar] [CrossRef]
  141. Ryan, J.; Storey, E.; Murray, A.M.; Woods, R.L.; Wolfe, R.; Reid, C.M.; Nelson, M.R.; Chong, T.T.; Williamson, J.D.; Ward, S.A.; et al. Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline. Neurology 2020, 95, E320–E331. [Google Scholar] [CrossRef]
  142. Li, H.; Li, W.; Zhang, X.; Ma, X.C.; Zhang, R.W. Aspirin Use on Incident Dementia and Mild Cognitive Decline: A Systematic Review and Meta-Analysis. Front. Aging Neurosci. 2021, 12, 578071. [Google Scholar] [CrossRef]
  143. Jordan, F.; Quinn, T.J.; McGuinness, B.; Passmore, P.; Kelly, J.P.; Tudur Smith, C.; Murphy, K.; Devane, D. Aspirin and other non-steroidal anti-inflammatory drugs for the prevention of dementia. Cochrane Database Syst. Rev. 2020, CD011459. [Google Scholar] [CrossRef]
  144. Rands, G.; Orrell, M. Aspirin for vascular dementia. Cochrane Database Syst. Rev. 2000, 2012, CD001296. [Google Scholar] [CrossRef]
  145. Jaturapatporn, D.; Mgekn, I.; Mccleery, J.; Tabet, N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst. Rev. 2012, 2, CD006378. [Google Scholar] [CrossRef]
  146. Veronese, N.; Stubbs, B.; Maggi, S.; Thompson, T.; Schofield, P.; Muller, C.; Tseng, P.; Lin, P.; Carvalho, A.F.; Solmi, M. Low-Dose Aspirin Use and Cognitive Function in Older Age: A Systematic Review and Meta-analysis. J. Am. Geriatr. Soc. 2017, 65, 1763–1768. [Google Scholar] [CrossRef]
  147. Gottlieb, A.B. Tumor necrosis factor blockade: Mechanism of action. J. Investig. Dermatol. Symp. Proc. 2007, 12, 1–4. [Google Scholar] [CrossRef]
  148. Levin, A.D.; Wildenberg, M.E.; van den Brink, G.R. Mechanism of Action of Anti-TNF Therapy in Inflammatory Bowel Disease. J. Crohn’s Colitis 2016, 10, 989–997. [Google Scholar] [CrossRef]
  149. Mitoma, H.; Horiuchi, T.; Tsukamoto, H.; Ueda, N. Molecular mechanisms of action of anti-TNF-α agents—Comparison among therapeutic TNF-α antagonists. Cytokine 2018, 101, 56–63. [Google Scholar] [CrossRef]
  150. Kirman, I.; Whelan, R.L.; Nielsen, O.H. Infliximab: Mechanism of action beyond TNF-α neutralization in inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 2004, 16, 639–641. [Google Scholar] [CrossRef]
  151. Agnholt, J.; Kelsen, J.; Brandsborg, B.; Jakobsen, N.O.; Dahlerup, J.F. Increased production of granulocyte-macrophage colony-stimulating factor in Crohn’s disease—A possible target for infliximab treatment. Eur. J. Gastroenterol. Hepatol. 2004, 16, 649–655. [Google Scholar] [CrossRef]
  152. Vos, A.C.W.; Wildenberg, M.E.; Duijvestein, M.; Verhaar, A.P.; Van Den Brink, G.R.; Hommes, D.W. AntiTumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 2011, 140, 221–230.e3. [Google Scholar] [CrossRef] [PubMed]
  153. Gottlieb, A.B.; Chamian, F.; Masud, S.; Cardinale, I.; Abello, M.V.; Lowes, M.A.; Chen, F.; Magliocco, M.; Krueger, J.G. TNF Inhibition Rapidly Down-Regulates Multiple Proinflammatory Pathways in Psoriasis Plaques. J. Immunol. 2005, 175, 2721–2729. [Google Scholar] [CrossRef]
  154. Ou, W.; Yang, J.; Simanauskaite, J.; Choi, M.; Castellanos, D.M.; Chang, R.; Sun, J.; Jagadeesan, N.; Parfitt, K.D.; Cribbs, D.H.; et al. Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy. J. Neuroinflamm. 2021, 18, 312. [Google Scholar] [CrossRef]
  155. Chang, R.; Knox, J.; Chang, J.; Derbedrossian, A.; Vasilevko, V.; Cribbs, D.; Boado, R.J.; Pardridge, W.M.; Sumbria, R.K. Blood-Brain Barrier Penetrating Biologic TNF-α Inhibitor for Alzheimer’s Disease. Mol. Pharm. 2017, 14, 2340–2349. [Google Scholar] [CrossRef]
  156. Abdelhamid, Y.A.; Elyamany, M.F.; Al-Shorbagy, M.Y.; Badary, O.A. Effects of TNF-α antagonist infliximab on fructose-induced metabolic syndrome in rats. Hum. Exp. Toxicol. 2021, 40, 801–811. [Google Scholar] [CrossRef]
  157. Shi, J.Q.; Shen, W.; Chen, J.; Wang, B.R.; Zhong, L.L.; Zhu, Y.W.; Zhu, H.-Q.; Zhang, Q.-Q.; Zhang, Y.-D.; Xu, J. Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res. 2011, 1368, 239–247. [Google Scholar] [CrossRef]
  158. Xu, J.J.; Guo, S.; Xue, R.; Xiao, L.; Kou, J.N.; Liu, Y.Q.; Han, J.-Y.; Fu, J.-J.; Wei, N. Adalimumab ameliorates memory impairments and neuroinflammation in chronic cerebral hypoperfusion rats. Aging 2021, 13, 14001–14014. [Google Scholar] [CrossRef]
  159. Chou, R.C.; Kane, M.; Ghimire, S.; Gautam, S.; Gui, J. Treatment for Rheumatoid Arthritis and Risk of Alzheimer’s Disease: A Nested Case-Control Analysis. CNS Drugs 2016, 30, 1111–1120. [Google Scholar] [CrossRef]
  160. Zhou, M.; Xu, R.; Kaelber, D.C.; Gurney, M.E. Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS ONE 2020, 15, e0229819. [Google Scholar] [CrossRef]
  161. Zhao, J.; Li, T.; Wang, J. Association between psoriasis and dementia: A systematic review. Neurologia 2021. Online ahead of print. [Google Scholar]
  162. Trzeciak, P.; Herbet, M.; Dudka, J. Common Factors of Alzheimer’s Disease and Rheumatoid Arthritis—Pathomechanism and Treatment. Molecules 2021, 26, 6038. [Google Scholar] [CrossRef] [PubMed]
  163. Lin, T.M.; Chen, W.S.; Sheu, J.J.; Chen, Y.H.; Chen, J.H.; Chang, C.C. Autoimmune rheumatic diseases increase dementia risk in middle-aged patients: A nationwide cohort study. PLoS ONE 2018, 13, e0186475. [Google Scholar] [CrossRef] [PubMed]
  164. Jin, L.W.; Lucente, J.D.; Nguyen, H.M.; Singh, V.; Singh, L.; Chavez, M.; Bushong, T.; Wulff, H.; Maezawa, I. Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer’s disease. Ann. Clin. Transl. Neurol. 2019, 6, 723–738. [Google Scholar] [CrossRef] [PubMed]
Figure 1. SARS-CoV-2 infection impacts the CNS via several potential pathways: (1) Infection of endothelial cells by viral particles present in the blood; (2) infiltration of the CNS by activated leukocytes from the bloodstream; (3) entrance of pro-inflammatory cytokines into the CNS; (4) loss of the BBB integrity due to increased immune response; (5) hypothetic direct passage of viral particles via olfactory nerve and (6) activation of pro-inflammatory phenotypes of CNS-residing cells.
Figure 1. SARS-CoV-2 infection impacts the CNS via several potential pathways: (1) Infection of endothelial cells by viral particles present in the blood; (2) infiltration of the CNS by activated leukocytes from the bloodstream; (3) entrance of pro-inflammatory cytokines into the CNS; (4) loss of the BBB integrity due to increased immune response; (5) hypothetic direct passage of viral particles via olfactory nerve and (6) activation of pro-inflammatory phenotypes of CNS-residing cells.
Cells 11 02959 g001
Table 1. Summary of findings associated with diet and inflammation.
Table 1. Summary of findings associated with diet and inflammation.
Study (Type)OutcomesDiet/InterventionGroupKey Findings
Ostan et al., 2015 [126]
(cohort study)
Inflammatory and metabolic parameters RISTOMED diet (personalized and balanced)
+/− nutraceutics
125 participantsRISTOMED diet alone or with each nutraceutical supplementation significantly decreased erythrocyte sedimentation rate
Kim et al., 2022 [127]
(non-randomized intervention study)
Inflammatory parameters
Insulin sensitivity
Short-term ketogenic diet (3 days)15 participantsShort-term Ketogenic diet resulted in lower IL-1β and TNF secretion;
Improved insulin sensitivity
Al-Abauidy et al., 2021 [128]
(randomized clinical trial)
Oxidative stress and inflammatory parametersMediterranean diet (12 weeks)19 participantsMediterranean diet reduced IL-6 levels by 49% and levels of oxidative stress marker, 8-OHdG, by 32.4%
Georgoulis et al., 2021 [129]
(randomized clinical trial)
Oxidative stress and inflammatory parametersMediterranean diet (6 months)187 patients with obstructive sleep apneaMediterranean diet reduced hs-CRP levels in patients
Casas et al., 2017 [132]
(randomized clinical trial)
Cytokine levelsMediterranean diet +/− extra virgin olive oil (5 years)66 participantsMediterranean diet reduced IL-6, IL-8, MCP-1, and MIP-1β levels. Addition of extra virgin olive oil reduced IL-1β, IL-5, IL-7, IL-12p70, IL-18, TNF-α, IFN-γ, GCSF, GMCSF, and ENA78
Omorogieva et al., 2021 [130]
(meta-analysis)
Lipid profiles, LPS, BMI, inflammatory markersDiet rich in fiber10 studies included in meta-analysisDietary fiber reduces total cholesterol, BMI and CRP, but no significant changes were observed for IL-6 and TNF
Shivappa et al., 2016 [131]
(cross-sectional study)
Inflammatory markers-532 adolescentsHigher dietary inflammatory index scores were associated with increased levels of various inflammatory markers: TNF-α, IL-1, 2, IFN-γ and VCAM
Mazzoli et al., 2020 [133]
(animal study)
Inflammatory markers, insulin sensitivity, BDNFWestern diet (4 weeks)16 ratsWestern diet increased TNF levels in white adipose tissue and hippocampus of rats; brain BDNF and synaptotagmin I were decreased, while PSD-95 was increased.
Jena et al., 2020 [134]
(animal study)
Interleukin-17, PD-95, BDNFHigh sugar and high fat diet (FPC diet) for 3 months, and 5 months +/− inulin supplementation12 miceFPC diet elevated RORγ and IL-17A signaling. Accompanied by microglia activation and reduced hippocampal long-term potentiation, FPC diet intake also reduced postsynaptic density-95 and brain derived neurotrophic factor.
Godfrey et al., 2020 [135]
(animal study)
CRP levels, CSF dopamine concentrations
Functional connectivity
12 months of obesogenic diet34 female rhesus monkeysCSF dopamine concentrations decreased, and CRP concentrations increased. Resting-state magnetic resonance neuroimaging showed that higher CRP concentrations were associated with decreased functional connectivity.
Table 2. Updates on clinical trials with the use of agents which potentially reduce neuroinflammation.
Table 2. Updates on clinical trials with the use of agents which potentially reduce neuroinflammation.
Anti-Inflammatory AgentClinicaltrial.gov IndentifierClinical Trial PhaseResults
Etanercept
(TNF antagonist)
NCT01068353, NCT01716637, NCT00203359, NCT002033201–2Etanercept was well tolerated and showed some trends toward cognitive, functional, and behavioral benefits
XPro1595/DN-TNF
(TNF antagonist)
NCT03943264, NCT05321498, NCT05522387, NCT053189761,2In phase 1 XPro1595 reduced white matter free water and increased the axonal integrity in adults with mild to moderate Alzheimer’s disease with signs of inflammation.
Phase 2 trials are currently active
Dapagliflozin
(selective sodium-glucose cotransporter 2 inhibitor)
NCT038016421/2Trial ongoing;
Alongside beneficial metabolic effects a potential anti-inflammatory effect via reduction in oxidative stress
ALZT-OP1/cromolyn + ibuprofen
(mast cell stabilizer + NSAID)
NCT04570644, NCT025478181/2, 3The combination of cromolyn and ibuprofen was safe and well tolerated. The concentrations of cromolyn and ibuprofen observed in the CSF are considered sufficient to titrate the estimated daily amyloid production and the associated inflammatory response in patients with AD.
Phase 3 results are to be published.
Senicapoc
(KCa3.1 blocker)
NCT048042412Phase 2 trial is currently active.
Previous animal studies show reduced neuroinflammation, decreased cerebral amyloid load, and enhanced hippocampal neuronal plasticity [164].
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