Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Neuroinflammatory Processes in Neurodegenerative Diseases

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (1 July 2022) | Viewed by 38841

Share This Special Issue

Special Issue Editors

Prof. Dr. Fabrizio Michetti

E-Mail
Collection Editor

Department of Neuroscience, Università Cattolica S. Cuore, Rome, Italy
Interests: neurodegeneration; neuroinflammation; multiple sclerosis; amyotrophic lateral sclerosis; animal models of neural diseases; neural biomarkers; calcium-binding neuroproteins; S100B protein
Special Issues, Collections and Topics in MDPI journals

Dr. Gabriele Di Sante

E-Mail
Collection Editor

Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy, University of Perugia, 06132 Perugia, Italy
Interests: neurodegeneration; neuroinflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pathological conditions of the nervous system in which neurons degenerate are collectively defined as neurodegenerative diseases. Different diseases are developed, essentially depending on the location of the neuronal population(s) involved. Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and multiple sclerosis are among the most pressing neurodegenerative diseases, owing to their devastating consequences. Despite the different aetiologies, a growing role is recognized in processes collectively referred to as neuroinflammation. During these processes neuron environment is affected, principally by non-neuronal neural cells, such as microglia and astrocytes, and also the blood–brain barrier, immune cells entering the nervous system, which mediate damage and repair. In this respect, emerging evidence also indicates that trillions of microorganisms that inhabit the gut (gut microbiota), may influence neuroinflammatory responses. They represent the most relevant source of proteins, pathogen-related motives, and “foreign” DNAs, continuously interacting with the immune system.

This Special Issue will provide an up-to-date overview, gathering research or review manuscripts addressing inflammatory processes that mechanistically participate to induce different neurodegenerative diseases, including molecular signaling pathways, mechanisms able to modulate immune cell trafficking, the role of microbiota, also considering the role of environment and genetics as drivers. Studies on inflammatory biomarkers as tools for diagnosing/monitoring neurodegenerative diseases are also welcome.

Prof. Dr. Fabrizio Michetti
Dr. Gabriele Di Sante
Collection Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neuroinflammation
neurodegeneration
astrocytes
microglia
immune cells
blood–brain barrier
microbiota
damage/danger-associated molecular patterns
pattern recognition receptors

Published Papers (11 papers)

Download All Papers

Research

Jump to: Review

13 pages, 1345 KiB

Open AccessArticle

S100B Protein as a Therapeutic Target in Multiple Sclerosis: The S100B Inhibitor Arundic Acid Protects from Chronic Experimental Autoimmune Encephalomyelitis

by Chiara Camponeschi, Maria De Carluccio, Susanna Amadio, Maria Elisabetta Clementi, Beatrice Sampaolese, Cinzia Volonté, Maria Tredicine, Vincenzo Romano Spica, Rosa Di Liddo, Francesco Ria, Fabrizio Michetti and Gabriele Di Sante

Int. J. Mol. Sci. 2021, 22(24), 13558; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413558 - 17 Dec 2021

Cited by 15 | Viewed by 3103

Abstract

S100B is an astrocytic protein behaving at high concentration as a damage-associated molecular pattern molecule. A direct correlation between the increased amount of S100B and inflammatory processes has been demonstrated, and in particular, the inhibitor of S100B activity pentamidine has been shown to ameliorate clinical scores and neuropathologic-biomolecular parameters in the relapsing-remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This study investigates the effect of arundic acid (AA), a known inhibitor of astrocytic S100B synthesis, in the chronic experimental autoimmune encephalomyelitis, which is another mouse model of multiple sclerosis usually studied. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the spinal cord, we observed that the AA-treated group showed lower severity compared to the vehicle-treated mice, particularly in the early phase of disease onset. We also observed a significant reduction of astrocytosis, demyelination, immune infiltrates, proinflammatory cytokines expression and enzymatic oxidative reactivity in the AA-treated group. Overall, our results reinforce the involvement of S100B in the development of animal models of multiple sclerosis and propose AA targeting the S100B protein as a focused potential drug to be considered for multiple sclerosis treatment. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Figure 1

16 pages, 2969 KiB

Open AccessArticle

Reduced Immunosenescence of Peripheral Blood T Cells in Parkinson’s Disease with CMV Infection Background

by Julia D. Vavilova, Anna A. Boyko, Natalya V. Ponomareva, Vitaly F. Fokin, Ekaterina Y. Fedotova, Maria A. Streltsova, Sofya A. Kust, Maria V. Grechikhina, Ekaterina V. Bril, Olga S. Zimnyakova, Elena I. Kovalenko and Alexander M. Sapozhnikov

Int. J. Mol. Sci. 2021, 22(23), 13119; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313119 - 04 Dec 2021

Cited by 8 | Viewed by 2516

Abstract

Immunosenescence is a process of remodeling the immune system under the influence of chronic inflammation during aging. Parkinson’s disease (PD) is a common age-associated neurodegenerative disorder and is frequently accompanied by neuroinflammation. On the other hand, cytomegalovirus (CMV), one of the most spread infections in humans, may induce chronic inflammation which contributes to immunosenescence, differentiation and the inflation of T cells and NK cells. Currently, there is no clear understanding of immunosenescence severity in PD patients infected with CMV. In this study, we analyzed differentiation stages and immunosenescence characteristics of T cells and NK cells in 31 patients with mild and moderate PD severity, 33 age-matched and 30 young healthy donors. The PD patients were 100% CMV-seropositive compared to 76% age-matched and 73% young CMV-infected healthy donors. The proportion of effector memory T cells re-expressing CD45RA, CD57⁺CD56⁻ T cells and CD57⁺CD56⁺ T cells was significantly reduced in PD patients compared with CMV-seropositive age-matched healthy individuals. The CD57⁺CD56⁻ T cell proportion in PD patients was similar to that of CMV-seropositive young healthy donors. Thus, PD is characterized by reduced peripheral blood T cell immunosenescence, even against the background of CMV infection. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Figure 1

18 pages, 7983 KiB

Open AccessArticle

Pioglitazone Ameliorates Lipopolysaccharide-Induced Behavioral Impairment, Brain Inflammation, White Matter Injury and Mitochondrial Dysfunction in Neonatal Rats

by Jiann-Horng Yeh, Kuo-Ching Wang, Asuka Kaizaki, Jonathan W. Lee, Han-Chi Wei, Michelle A. Tucci, Norma B. Ojeda, Lir-Wan Fan and Lu-Tai Tien

Int. J. Mol. Sci. 2021, 22(12), 6306; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126306 - 11 Jun 2021

Cited by 14 | Viewed by 2934

Abstract

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. The present study was conducted to examine whether pioglitazone can reduce impairment of behavioral deficits mediated by inflammatory-induced brain white matter injury in neonatal rats. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 2 mg/kg) was administered to Sprague–Dawley rat pups on postnatal day 5 (P5), and i.p. administration of pioglitazone (20 mg/kg) or vehicle was performed 5 min after LPS injection. Sensorimotor behavioral tests were performed 24 h after LPS exposure, and changes in biochemistry of the brain was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, reduction of oligodendrocytes and mitochondrial activity, and increases in lipid peroxidation and brain inflammation, as indicated by the increment of interleukin-1β (IL-1β) levels and number of activated microglia in the neonatal rat brain. Pioglitazone treatment significantly improved LPS-induced neurobehavioral and physiological disturbances including the loss of body weight, hypothermia, righting reflex, wire-hanging maneuver, negative geotaxis, and hind-limb suspension in neonatal rats. The neuroprotective effect of pioglitazone against the loss of oligodendrocytes and mitochondrial activity was associated with attenuation of LPS-induced increment of thiobarbituric acid reactive substances (TBARS) content, IL-1β levels and number of activated microglia in neonatal rats. Our results show that pioglitazone prevents neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on microglial activation, IL-1β induction, lipid peroxidation, oligodendrocyte production and mitochondrial activity. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Figure 1

13 pages, 10629 KiB

Open AccessArticle

Interleukin-13 Propagates Prothrombin Kringle-2-Induced Neurotoxicity in Hippocampi In Vivo via Oxidative Stress

by Jae Yeong Jeong, Rayul Wi, Young Cheul Chung and Byung Kwan Jin

Int. J. Mol. Sci. 2021, 22(7), 3486; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073486 - 27 Mar 2021

Cited by 6 | Viewed by 1821

Abstract

The present study investigated expression of endogenous interleukin-13 (IL-13) and its possible function in the hippocampus of prothrombin kringle-2 (pKr-2)-lesioned rats. Here we report that intrahippocampal injection of pKr-2 revealed a significant loss of NeuN-immunopositive (NeuN⁺) and Nissl⁺ cells in the hippocampus at 7 days after pKr-2. In parallel, pKr-2 increased IL-13 levels, which reached a peak at 3 days post pKr-2 and sustained up to 7 days post pKr-2. IL-13 immunoreactivity was seen exclusively in activated microglia/macrophages and neutrophils, but not in neurons or astrocytes. In experiments designed to explore the involvement of IL-13 in neurodegeneration, IL-13 neutralizing antibody (IL-13Nab) significantly increased survival of NeuN⁺ and Nissl⁺ cells. Accompanying neuroprotection, immunohistochemical analysis indicated that IL-13Nab inhibited pKr-2-induced expression of inducible nitric oxide synthase and myeloperoxidase within activated microglia/macrophages and neutrophils, possibly resulting in attenuation of reactive oxygen species (ROS) generation and oxidative damage of DNA and protein. The current findings suggest that the endogenous IL-13 expressed in pKr-2 activated microglia/macrophages and neutrophils might be harmful to hippocampal neurons via oxidative stress. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Figure 1

26 pages, 3813 KiB

Open AccessArticle

Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia

by Katarzyna Chamera, Ewa Trojan, Katarzyna Kotarska, Magdalena Szuster-Głuszczak, Natalia Bryniarska, Kinga Tylek and Agnieszka Basta-Kaim

Int. J. Mol. Sci. 2021, 22(4), 1558; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041558 - 04 Feb 2021

Cited by 15 | Viewed by 3840

Abstract

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the “two-hit” hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIA_PPI-low and MIA_PPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIA_PPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the “second hit” in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Figure 1

21 pages, 2914 KiB

Open AccessArticle

Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer’s Disease

by Leela Paladugu, Abeer Gharaibeh, Nivya Kolli, Cameron Learman, Tia C. Hall, Lixin Li, Julien Rossignol, Panchanan Maiti and Gary L. Dunbar

Int. J. Mol. Sci. 2021, 22(2), 860; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020860 - 16 Jan 2021

Cited by 32 | Viewed by 4499

Abstract

Recent clinical and epidemiological studies support the contention that diabetes mellitus (DM) is a strong risk factor for the development of Alzheimer’s disease (AD). The use of insulin cell toxin, streptozotocin (STZ), when injected into the lateral ventricles, develops an insulin resistant brain state (IRBS) and represents a non-transgenic, or sporadic AD model (SAD), with several AD-like neuropathological features. The present study explored the effects of an anti-diabetic drug, liraglutide (LIR), in reversing major pathological hallmarks in the prodromal disease stage of both the 5xFAD transgenic and SAD mouse models of AD. Three-month-old 5xFAD and age-matched wild type mice were given a single intracerebroventricular (i.c.v) injection of STZ or vehicle (saline) and were subsequently treated with LIR, intraperitoneally (IP), once a day for 30 days. The extent of neurodegeneration, Aβ plaque load, and key proteins associated with the insulin signaling pathways were measured using Western blot and neuroinflammation (via immunohistological assays) in the cortical and hippocampal regions of the brain were assessed following a series of behavioral tests used to measure cognitive function after LIR or vehicle treatments. Our results indicated that STZ significantly increased neuroinflammation, Aβ plaque deposition and disrupted insulin signaling pathway, while 25 nmol/kg LIR, when injected IP, significantly decreased neuroinflammatory responses in both SAD and 5xFAD mice before significant cognitive changes were observed, suggesting LIR can reduce early neuropathology markers prior to the emergence of overt memory deficits. Our results indicate that LIR has neuroprotective effects and has the potential to serve as an anti-inflammatory and anti-amyloid prophylactic therapy in the prodromal stages of AD. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Figure 1

15 pages, 2898 KiB

Open AccessArticle

Solid Lipid Curcumin Particles Protect Medium Spiny Neuronal Morphology, and Reduce Learning and Memory Deficits in the YAC128 Mouse Model of Huntington’s Disease

by Abeer Gharaibeh, Panchanan Maiti, Rebecca Culver, Shiela Heileman, Bhairavi Srinageshwar, Darren Story, Kristin Spelde, Leela Paladugu, Nikolas Munro, Nathan Muhn, Nivya Kolli, Julien Rossignol and Gary L. Dunbar

Int. J. Mol. Sci. 2020, 21(24), 9542; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249542 - 15 Dec 2020

Cited by 10 | Viewed by 3206

Abstract

Huntington’s disease (HD) is a genetic neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms, accompanied by massive neuronal degeneration in the striatum. In this study, we utilized solid lipid curcumin particles (SLCPs) and solid lipid particles (SLPs) to test their efficacy in reducing deficits in YAC128 HD mice. Eleven-month-old YAC128 male and female mice were treated orally with SLCPs (100 mg/kg) or equivalent volumes of SLPs or vehicle (phosphate-buffered saline) every other day for eight weeks. Learning and memory performance was assessed using an active-avoidance task on week eight. The mice were euthanized, and their brains were processed using Golgi-Cox staining to study the morphology of medium spiny neurons (MSNs) and Western blots to quantify amounts of DARPP-32, brain-derived neurotrophic factor (BDNF), TrkB, synaptophysin, and PSD-95. We found that both SLCPs and SLPs improved learning and memory in HD mice, as measured by the active avoidance task. We also found that SLCP and SLP treatments preserved MSNs arborization and spinal density and modulated synaptic proteins. Our study shows that SLCPs, as well as the lipid particles, can have therapeutic effects in old YAC128 HD mice in terms of recovering from HD brain pathology and cognitive deficits. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Figure 1

26 pages, 6519 KiB

Open AccessArticle

Ameliorative Properties of Boronic Compounds in In Vitro and In Vivo Models of Alzheimer’s Disease

by Panchanan Maiti, Jayeeta Manna, Zoe N. Burch, Denise B. Flaherty, Joseph D. Larkin and Gary L. Dunbar

Int. J. Mol. Sci. 2020, 21(18), 6664; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186664 - 11 Sep 2020

Cited by 23 | Viewed by 3022

Abstract

Alzheimer’s disease (AD) is characterized by amyloid (Aβ) aggregation, hyperphosphorylated tau, neuroinflammation, and severe memory deficits. Reports that certain boronic compounds can reduce amyloid accumulation and neuroinflammation prompted us to compare trans-2-phenyl-vinyl-boronic-acid-MIDA-ester (TPVA) and trans-beta-styryl-boronic-acid (TBSA) as treatments of deficits in in vitro and in vivo models of AD. We hypothesized that these compounds would reduce neuropathological deficits in cell-culture and animal models of AD. Using a dot-blot assay and cultured N₂a cells, we observed that TBSA inhibited Aβ42 aggregation and increased cell survival more effectively than did TPVA. These TBSA-induced benefits were extended to C. elegans expressing Aβ42 and to the 5xFAD mouse model of AD. Oral administration of 0.5 mg/kg dose of TBSA or an equivalent amount of methylcellulose vehicle to groups of six- and 12-month-old 5xFAD or wild-type mice over a two-month period prevented recognition- and spatial-memory deficits in the novel-object recognition and Morris-water-maze memory tasks, respectively, and reduced the number of pyknotic and degenerated cells, Aβ plaques, and GFAP and Iba-1 immunoreactivity in the hippocampus and cortex of these mice. These findings indicate that TBSA exerts neuroprotective properties by decreasing amyloid plaque burden and neuroinflammation, thereby preventing neuronal death and preserving memory function in the 5xFAD mice. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Graphical abstract

22 pages, 5870 KiB

Open AccessArticle

P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures

by Duk-Shin Lee and Ji-Eun Kim

Int. J. Mol. Sci. 2020, 21(18), 6476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186476 - 04 Sep 2020

Cited by 13 | Viewed by 2879

Abstract

Recently, we have reported that blockade/deletion of P2X7 receptor (P2X7R), an ATP-gated ion channel, exacerbates heat shock protein 25 (HSP25)-mediated astroglial autophagy (clasmatodendrosis) following kainic acid (KA) injection. In P2X7R knockout (KO) mice, prolonged astroglial HSP25 induction exerts 5′ adenosine monophosphate-activated protein kinase/unc-51 like autophagy activating kinase 1-mediated autophagic pathway independent of mammalian target of rapamycin (mTOR) activity following KA injection. Sustained HSP25 expression also enhances AKT-serine (S) 473 phosphorylation leading to astroglial autophagy via glycogen synthase kinase-3β/bax interacting factor 1 signaling pathway. However, it is unanswered how P2X7R deletion induces AKT-S473 hyperphosphorylation during autophagic process in astrocytes. In the present study, we found that AKT-S473 phosphorylation was increased by enhancing activity of focal adhesion kinase (FAK), independent of mTOR complex (mTORC) 1 and 2 activities in isolated astrocytes of P2X7R knockout (KO) mice following KA injection. In addition, HSP25 overexpression in P2X7R KO mice acted as a chaperone of AKT, which retained AKT-S473 phosphorylation by inhibiting the pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1- and 2-binding to AKT. Therefore, our findings suggest that P2X7R may be a fine-tuner of AKT-S473 activity during astroglial autophagy by regulating FAK phosphorylation and HSP25-mediated inhibition of PHLPP1/2-AKT binding following KA treatment. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Graphical abstract

Review

Jump to: Research

21 pages, 3341 KiB

Open AccessReview

Locus Coeruleus Modulates Neuroinflammation in Parkinsonism and Dementia

by Filippo Sean Giorgi, Francesca Biagioni, Alessandro Galgani, Nicola Pavese, Gloria Lazzeri and Francesco Fornai

Int. J. Mol. Sci. 2020, 21(22), 8630; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228630 - 16 Nov 2020

Cited by 31 | Viewed by 4420

Abstract

Locus Coeruleus (LC) is the main noradrenergic nucleus of the central nervous system, and its neurons widely innervate the whole brain. LC is severely degenerated both in Alzheimer’s disease (AD) and in Parkinson’s disease (PD), years before the onset of clinical symptoms, through mechanisms that differ among the two disorders. Several experimental studies have shown that noradrenaline modulates neuroinflammation, mainly by acting on microglia/astrocytes function. In the present review, after a brief introduction on the anatomy and physiology of LC, we provide an overview of experimental data supporting a pathogenetic role of LC degeneration in AD and PD. Then, we describe in detail experimental data, obtained in vitro and in vivo in animal models, which support a potential role of neuroinflammation in such a link, and the specific molecules (i.e., released cytokines, glial receptors, including pattern recognition receptors and others) whose expression is altered by LC degeneration and might play a key role in AD/PD pathogenesis. New imaging and biochemical tools have recently been developed in humans to estimate in vivo the integrity of LC, the degree of neuroinflammation, and pathology AD/PD biomarkers; it is auspicable that these will allow in the near future to test the existence of a link between LC-neuroinflammation and neurodegeneration directly in patients. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures

Figure 1

19 pages, 1339 KiB

Open AccessReview

Microglial Phagocytosis—Rational but Challenging Therapeutic Target in Multiple Sclerosis

by Maria V. Pinto and Adelaide Fernandes

Int. J. Mol. Sci. 2020, 21(17), 5960; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21175960 - 19 Aug 2020

Cited by 16 | Viewed by 5331

Abstract

Multiple sclerosis (MS) is the most common autoimmune and demyelinating disease of the central nervous system (CNS), characterized, in the majority of cases, by initial relapses that later evolve into progressive neurodegeneration, severely impacting patients’ motor and cognitive functions. Despite the availability of immunomodulatory therapies effective to reduce relapse rate and slow disease progression, they all failed to restore CNS myelin that is necessary for MS full recovery. Microglia are the primary inflammatory cells present in MS lesions, therefore strongly contributing to demyelination and lesion extension. Thus, many microglial-based therapeutic strategies have been focused on the suppression of microglial pro-inflammatory phenotype and neurodegenerative state to reduce disease severity. On the other hand, the contribution of myelin phagocytosis advocating the neuroprotective role of microglia in MS has been less explored. Indeed, despite the presence of functional oligodendrocyte precursor cells (OPCs), within lesioned areas, MS plaques fail to remyelinate as a result of the over-accumulation of myelin-toxic debris that must be cleared away by microglia. Dysregulation of this process has been associated with the impaired neuronal recovery and deficient remyelination. In line with this, here we provide a comprehensive review of microglial myelin phagocytosis and its involvement in MS development and repair. Alongside, we discuss the potential of phagocytic-mediated therapeutic approaches and encourage their modulation as a novel and rational approach to ameliorate MS-associated pathology. Full article

(This article belongs to the Special Issue Neuroinflammatory Processes in Neurodegenerative Diseases)

► Show Figures