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The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 27965

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Dr. Dolores Viña

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Research Group of Chronic Diseases Pharmacology, Center for Research in Molecular Medicine and Chronic Diseases(CIMUS), Universidade de Santiago de Compostela, Avda. de Barcelona, 15782 Santiago de Compostela, A Coruña, Spain
Interests: neurodegenerative diseases; endothelial dysfunction; inflammation; oxidative stress; drug development
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Special Issue Information

Dear Colleagues,

The contribution of chronic peripheral inflammation to the pathogenesis of neurodegenerative diseases is currently a matter of debate. A wide range of pathologies, such as chronic infections, autoimmune and metabolic diseases, or vascular endothelial dysfunction, among others, cause sustained activation of the innate and adaptive peripheral immune systems. In addition, low-grade chronic inflammation occurs during aging even in the absence of other pathologies, which has been called "inflammaging". Peripheral inflammation is recognized as a prominent feature contributing to the disruption of the brain-blood barrier (BBB) by various pathways resulting in several CNS disease progressions. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease all share a pervasive feature: chronic aberrant inflammation. Despite the recognized benefits of neuroinflammation in the CNS, activation of microglia in the brain contributes to neurotoxicity, oxidative stress, and synaptic and neuronal damage.

In this Special Issue, we welcome the submission of original research manuscripts, as well as review articles focusing on the possible contribution of chronic peripheral inflammation to the pathogenesis of neurodegenerative diseases with a focus on microglia and astrocytes activation. Specifically, articles including the following topics will be welcome:

Crosstalk between Chronic Peripheral Inflammation and microglia and astrocytes activation;
Inflammation caused by chronic infections, autoimmune and metabolic diseases (obesity, diabetes) and hypertension and their relationship with neurodegenerative diseases;
Gut microbiome and inflammation in neurodegeneration;
Inflammaging and neurodegeneration;
BBB dysfunction in neurodegenerative disorders;
Blood or other biomarkers of neuroinflammation with respect to neurodegeneration;
Drug development for neurodegenerative disorders based on chronic peripheral inflammation treatment.

Dr. Dolores Viña
Guest Editor

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Keywords

peripheral inflammation
neuroinflammation
brain-blood barrier
neurodegenerative disorders
biomarkers

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Published Papers (9 papers)

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Research

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17 pages, 3595 KiB

Open AccessArticle

Effects of Sodium Nitroprusside on Lipopolysaccharide-Induced Inflammation and Disruption of Blood–Brain Barrier

by Nuria Seoane, Aitor Picos, Sandra Moraña-Fernández, Martina Schmidt, Amalia Dolga, Manuel Campos-Toimil and Dolores Viña

Cells 2024, 13(10), 843; https://doi.org/10.3390/cells13100843 - 15 May 2024

Viewed by 1173

Abstract

In various neurodegenerative conditions, inflammation plays a significant role in disrupting the blood–brain barrier (BBB), contributing to disease progression. Nitric oxide (NO) emerges as a central regulator of vascular function, with a dual role in inflammation, acting as both a pro- and anti-inflammatory molecule. This study investigates the effects of the NO donor sodium nitroprusside (SNP) in protecting the BBB from lipopolysaccharide (LPS)-induced inflammation, using bEnd.3 endothelial cells as a model system. Additionally, Raw 264.7 macrophages were employed to assess the effects of LPS and SNP on their adhesion to a bEnd.3 cell monolayer. Our results show that LPS treatment induces oxidative stress, activates the JAK2/STAT3 pathway, and increases pro-inflammatory markers. SNP administration effectively mitigates ROS production and IL-6 expression, suggesting a potential anti-inflammatory role. However, SNP did not significantly alter the adhesion of Raw 264.7 cells to bEnd.3 cells induced by LPS, probably because it did not have any effect on ICAM-1 expression, although it reduced VCAM expression. Moreover, SNP did not prevent BBB disruption. This research provides new insights into the role of NO in BBB disruption induced by inflammation. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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13 pages, 2143 KiB

Open AccessArticle

Retinal Injury Activates Complement Expression in Müller Cells Leading to Neuroinflammation and Photoreceptor Cell Death

by Steven J. Tabor, Kentaro Yuda, Jonathan Deck, Gopalan Gnanaguru and Kip M. Connor

Cells 2023, 12(13), 1754; https://doi.org/10.3390/cells12131754 - 30 Jun 2023

Viewed by 2448

Abstract

Retinal detachment (RD) is a neurodegenerative blinding disease caused by plethora of clinical conditions. RD is characterized by the physical separation of retina from the underlying retinal pigment epithelium (RPE), eventually leading to photoreceptor cell death, inflammation, and vision loss. Albeit the activation of complement plays a critical role in the pathogenesis of RD, the retinal cellular source for complement production remains elusive. Here, using C3 tdTomato reporter mice we show that retinal injury upregulates C3 expression, specifically in Müller cells. Activation of the complement cascade results in the generation of proinflammatory cleaved products, C3a and C5a, that bind C3aR and C5aR1, respectively. Our flow cytometry data show that retinal injury significantly upregulated C3aR and C5aR1 in microglia and resulted in the infiltration of peripheral immune cells. Loss of C3, C5, C3aR or C5aR1 reduced photoreceptor cell death and infiltration of microglia and peripheral immune cells into the sub-retinal space. These results indicate that C3/C3aR and C5/C5aR1 play a crucial role in eliciting photoreceptor degeneration and inflammatory responses in RD. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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14 pages, 3605 KiB

Open AccessArticle

Astrocytosis, Inflammation, Axonal Damage and Myelin Impairment in the Internal Capsule following Striatal Ischemic Injury

by Marco Aurelio M. Freire, Rafael Rodrigues Lima, Leonardo Oliveira Bittencourt, Joanilson S. Guimaraes, Daniel Falcao and Walace Gomes-Leal

Cells 2023, 12(3), 457; https://doi.org/10.3390/cells12030457 - 31 Jan 2023

Cited by 5 | Viewed by 2385

Abstract

Secondary degeneration is defined as a set of destructive events that damage cells and structures that were initially spared or only peripherally affected by the primary insult, constituting a key factor for functional impairment after traumatic brain injury or stroke. In the present study, we evaluated the patterns of astrocytosis, inflammatory response, axonal damage and oligodendrocytes/myelin impairment in the internal capsule following a focal injection of endothelin-1 (ET-1) into the dorsal striatum. Animals were perfused at 1, 3 and 7 post-lesion days (PLD), and tissue was processed to immunohistochemistry for neutrophils (MBS1), macrophages/microglia (ED1), astrocytes (GFAP), axonal lesion (βAPP), oligodendrocytes (Tau) and myelin (MBP). A significant number of neutrophils was observed at 1PLD, followed by intense recruitment/activation of macrophages/microglia at 3PLD and astrocytic reaction with a peak at 7PLD. Oligodendrocyte damage was pronounced at 3PLD, remaining at 7PLD. Progressive myelin impairment was observed, with reduction of immunoreactivity at 7PLD. Axonal lesion was also identified, mainly at 7PLD. Our results indicate that acute inflammatory response elicited by the ischemic insult in the striatum can be associated with the axonal impairment and damage of both oligodendrocytes and myelin sheath identified in the internal capsule, which may be related to loss of tissue functionality observed in secondary degeneration. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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19 pages, 16706 KiB

Open AccessArticle

Beneficial Effect of ACI-24 Vaccination on Aβ Plaque Pathology and Microglial Phenotypes in an Amyloidosis Mouse Model

by Jasenka Rudan Njavro, Marija Vukicevic, Emma Fiorini, Lina Dinkel, Stephan A. Müller, Anna Berghofer, Chiara Bordier, Stanislav Kozlov, Annett Halle, Katrin Buschmann, Anja Capell, Camilla Giudici, Michael Willem, Regina Feederle, Stefan F. Lichtenthaler, Chiara Babolin, Paolo Montanari, Andrea Pfeifer, Marie Kosco-Vilbois and Sabina Tahirovic

Cells 2023, 12(1), 79; https://doi.org/10.3390/cells12010079 - 24 Dec 2022

Cited by 4 | Viewed by 3444

Abstract

Amyloid-β (Aβ) deposition is an initiating factor in Alzheimer’s disease (AD). Microglia are the brain immune cells that surround and phagocytose Aβ plaques, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aβ targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aβ plaque load, Aβ plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Aβ plaques, we observed a more ramified morphology of Aβ plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Aβ plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Aβ targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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20 pages, 4346 KiB

Open AccessArticle

The NeuroinflammatoryPotential of HIV-1 NefVariants in Modulating the Gene Expression Profile of Astrocytes

by Sushama Jadhav, Prajakta Makar and Vijay Nema

Cells 2022, 11(20), 3256; https://doi.org/10.3390/cells11203256 - 17 Oct 2022

Cited by 3 | Viewed by 1752

Abstract

HIV-1 mediated neurotoxicity is thought to be associated with HIV-1 viral proteins activating astrocytes and microglia by inducing inflammatory cytokines leading to the development of HIV-associated neurocognitive disorder (HAND). In the current study, we observe how HIV-1 Nef upregulates the levels of IL-6, IP-10, and TNF-α around 6.0fold in normal human astrocytes (NHAs) compared to cell and empty vector controls. Moderate downregulation in the expression profile of inflammatory cytokines was observed due to RNA interference. Furthermore, we determine the impact of inflammatory cytokines in the upregulation of kynurenine pathway metabolites, such as indoleamine 2,3-dioxygenase (IDO), and 3-hydroxyanthranilic acid oxygenase (HAAO) in NHA, and found the same to be 3.0- and 3.2-fold, respectively. Additionally, the variation in the level of nitric oxide before and after RNA interference was significant. The upregulated cytokines and pathway-specific metabolites could be linked with the neurotoxic potential of HIV-1 Nef. Thus, the downregulation in cytokines and kynurenine metabolites observed after siRNA-Nef interference indicates the possibility of combining the RNA interference approach with current antiretroviral therapy to prevent neurotoxicity development. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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Review

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13 pages, 626 KiB

Open AccessReview

The Role of Gut Microbiome in the Pathogenesis of Multiple Sclerosis and Related Disorders

by Anna Dunalska, Kamila Saramak and Natalia Szejko

Cells 2023, 12(13), 1760; https://doi.org/10.3390/cells12131760 - 30 Jun 2023

Cited by 8 | Viewed by 4638

Abstract

Multiple sclerosis (MS) is a chronic, progressive neuroinflammatory disease with a complex pathophysiological background. A variety of diverse factors have been attributed to the propagation of inflammation and neurodegeneration in MS, mainly genetic, immunological, and environmental factors such as vitamin D deficiency, infections, or hormonal disbalance. Recently, the importance of the gut-brain axis for the development of many neurological conditions, including stroke, movement disorders, and neuroinflammatory disorders, has been postulated. The purpose of our paper was to summarize current evidence confirming the role of the gut microbiome in the pathophysiology of MS and related disorders, such as neuromyelitis optica spectrum disorder (NMO-SD). For this aim, we conducted a systematic review of the literature listed in the following databases: Medline, Pubmed, and Scopus, and were able to identify several studies demonstrating the involvement of the gut microbiome in the pathophysiology of MS and NMO-SD. It seems that the most relevant bacteria for the pathophysiology of MS are those belonging to Pseudomonas, Mycoplasma, Haemophilus, Blautia, Dorea, Faecalibacterium, Methanobrevibacter, Akkermansia, and Desulfovibrionaceae genera, while Clostridium perfringens and Streptoccocus have been demonstrated to play a role in the pathophysiology of NMO-SD. Following this line of evidence, there is also some preliminary data supporting the use of probiotics or other agents affecting the microbiome that could potentially have a beneficial effect on MS/NMO-SD symptoms and prognosis. The topic of the gut microbiome in the pathophysiology of MS is therefore relevant since it could be used as a biomarker of disease development and progression as well as a potential disease-modifying therapy. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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14 pages, 689 KiB

Open AccessReview

Thrombin, a Key Driver of Pathological Inflammation in the Brain

by Jaclyn Iannucci and Paula Grammas

Cells 2023, 12(9), 1222; https://doi.org/10.3390/cells12091222 - 23 Apr 2023

Cited by 10 | Viewed by 3914

Abstract

Neurodegenerative diseases, including Alzheimer’s disease (AD), are major contributors to death and disability worldwide. A multitude of evidence suggests that neuroinflammation is critical in neurodegenerative disease processes. Exploring the key mediators of neuroinflammation in AD, a prototypical neurodegenerative disease, could help identify pathologic inflammatory mediators and mechanisms in other neurodegenerative diseases. Elevated levels of the multifunctional inflammatory protein thrombin are commonly found in conditions that increase AD risk, including diabetes, atherosclerosis, and traumatic brain injury. Thrombin, a main driver of the coagulation cascade, has been identified as important to pathological events in AD and other neurodegenerative diseases. Furthermore, recent evidence suggests that coagulation cascade-associated proteins act as drivers of inflammation in the AD brain, and studies in both human populations and animal models support the view that abnormalities in thrombin generation promote AD pathology. Thrombin drives neuroinflammation through its pro-inflammatory activation of microglia, astrocytes, and endothelial cells. Due to the wide-ranging pro-inflammatory effects of thrombin in the brain, inhibiting thrombin could be an effective strategy for interrupting the inflammatory cascade which contributes to neurodegenerative disease progression and, as such, may be a potential therapeutic target for AD and other neurodegenerative diseases. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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20 pages, 1436 KiB

Open AccessReview

Mushroom Natural Products in Neurodegenerative Disease Drug Discovery

by Arjuna Abitbol, Brody Mallard, Evelin Tiralongo and Joe Tiralongo

Cells 2022, 11(23), 3938; https://doi.org/10.3390/cells11233938 - 6 Dec 2022

Cited by 7 | Viewed by 4181

Abstract

The variety of drugs available to treat neurodegenerative diseases is limited. Most of these drug’s efficacy is restricted by individual genetics and disease stages and usually do not prevent neurodegeneration acting long after irreversible damage has already occurred. Thus, drugs targeting the molecular mechanisms underlying subsequent neurodegeneration have the potential to negate symptom manifestation and subsequent neurodegeneration. Neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, and is associated with the activation of the NLRP3 inflammasome, which in turn leads to neurodegeneration. Inflammasome activation and oligomerisation is suggested to be a major driver of disease progression occurring in microglia. With several natural products and natural product derivatives currently in clinical trials, mushrooms have been highlighted as a rich and largely untapped source of biologically active compounds in both in vitro and in vivo neurodegenerative disease models, partially supported by successful clinical trial evaluations. Additionally, novel high-throughput methods for the screening of natural product compound libraries are being developed to help accelerate the neurodegenerative disease drug discovery process, targeting neuroinflammation. However, the breadth of research relating to mushroom natural product high-throughput screening is limited, providing an exciting opportunity for further detailed investigations. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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17 pages, 812 KiB

Open AccessReview

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

by Mateusz Łuc, Marta Woźniak and Joanna Rymaszewska

Cells 2022, 11(19), 2959; https://doi.org/10.3390/cells11192959 - 22 Sep 2022

Viewed by 2952

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. Full article

(This article belongs to the Special Issue The Role of Inflammation in Neurodegenerative Diseases and Its Therapeutic Prospects)

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