The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the ...last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.
Aims
According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we ...studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α‐synuclein (α‐syn) in the gastrointestinal tract and midbrain dopaminergic neurons.
Methods
We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS‐based rat model of gut inflammation in terms of α‐syn pathology.
Results
Our data support the existence of pathogenic α‐syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS‐based rat model of gut inflammation to demonstrate (i) the appearance of P‐α‐syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α‐syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD.
Conclusion
These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut‐brain axis in initiating α‐syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.
In this article, we include data demonstrating pathogenic insoluble phosphorylated α‐synuclein (P‐α‐syn) aggregates in the gastrointestinal tract from patients earlier diagnosed with inflammatory bowel disease (IBD). Using thioflavin‐S staining along with P‐α‐syn in the human midbrain of IBD cases, we have identified a group of highly depigmented neurons showing insoluble α‐syn aggregates. Using a rat model of IBD, we show that long‐lasting inflammation of the gastrointestinal tract leads to striking neuropathological features typically associated with Parkinson's disease.
J. Neurochem. (2010) 114, 1687-1700. Peripheral inflammation could play a role in the origin and development of certain neurodegenerative disorders. To ascertain this possibility, a model of ...dopaminergic neurodegeneration based on the injection of the inflammatory agent lipopolysaccharide (LPS) within the substantia nigra was assayed in rats with ulcerative colitis (UC) induced by the ingestion of dextran sulphate sodium. We found an increase in the levels of inflammatory markers from serum (tumor necrosis factor-α, IL-1β, IL-6 and the acute phase protein C-reactive protein) and substantia nigra (tumor necrosis factor-α, IL-1β, IL-6, inducible nitric oxide synthase, intercellular adhesion molecule-1, microglial and astroglial populations) of rats with UC, as well as an alteration of the blood-brain barrier permeability and the loss of dopaminergic neurons. UC reinforced the inflammatory and deleterious effects of LPS. On the contrary, clodronate encapsulated in liposomes (ClodLip), which depletes peripheral macrophages, ameliorated the effect of LPS and UC. Peripheral inflammation might represent a risk factor in the development of Parkinson's disease.
The advent of high-throughput single-cell transcriptomic analysis of microglia has revealed different phenotypes that are inherently associated with disease conditions. A common feature of some of ...these activated phenotypes is the upregulation of galectin-3. Representative examples of these phenotypes include disease-associated microglia (DAM) and white-associated microglia (WAM), whose role(s) in neuroprotection/neurotoxicity is a matter of high interest in the microglia community. In this review, we summarise the main findings that demonstrate the ability of galectin-3 to interact with key pattern recognition receptors, including, among others, TLR4 and TREM2 and the importance of galectin-3 in the regulation of microglia activation. Finally, we discuss increasing evidence supporting the involvement of this lectin in the main neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, and stroke.
Parkinson's disease is an irreversible neurodegenerative disease linked to progressive movement disorders and is accompanied by an inflammatory reaction that is believed to contribute to its ...pathogenesis. Since sensitivity to inflammation is not the same in all brain structures, the aim of this work was to test whether physiological conditions as stress could enhance susceptibility to inflammation in the substantia nigra, where death of dopaminergic neurons takes place in Parkinson's disease.
To achieve our aim, we induced an inflammatory process in nonstressed and stressed rats (subject to a chronic variate stress) by a single intranigral injection of lipopolysaccharide, a potent proinflammogen. The effect of this treatment was evaluated on inflammatory markers as well as on neuronal and glial populations.
Data showed a synergistic effect between inflammation and stress, thus resulting in higher microglial activation and expression of proinflammatory markers. More important, the higher inflammatory response seen in stressed animals was associated with a higher rate of death of dopaminergic neurons in the substantia nigra, the most characteristic feature seen in Parkinson's disease. This effect was dependent on glucocorticoids.
Our data demonstrate that stress sensitises midbrain microglia to further inflammatory stimulus. This suggests that stress may be an important risk factor in the degenerative processes and symptoms of Parkinson's disease.
Neurodegenerative diseases are characterized by a progressive deterioration of brain function, with a consequent significant decline in the quality of life of patients and their families. Due to the ...concurrent increase in life expectancy, the incidence of these diseases has been increasing over the last years and thus there is a growing interest in finding potential risk factors. This review focuses on the correlation between peripheral inflammatory diseases and neurodegeneration, in particular on the relationship between gastrointestinal disorders and Parkinson's disease, especially through the so called gut-brain axis.
Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including ...cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease.
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•Metformin treatment decreases microglial activation in the MPTP model of Parkinson's disease.•Metformin treatment increases the neurodegeneration in the MPTP model of Parkinson's disease, both in vivo and vitro.•Metformin treatment could be a risk factor for the development of Parkinson's disease.
Neuroinflammation is a common feature shared by neurodegenerative disorders, such as Parkinson's disease (PD), and seems to play a key role in their development and progression. Microglia cells, the ...principal orchestrators of neuroinflammation, can be polarized in different phenotypes, which means they are able to have anti-inflammatory, pro-inflammatory, or neurodegenerative effects. Increasing evidence supports that the traditional Mediterranean dietary pattern is related to the reduction of cognitive decline in neurodegenerative diseases. A considerable intake of plant foods, fish, and extra virgin olive oil (EVOO), as well as a moderate consumption of red wine, all characteristic of the Mediterranean diet (MD), are behind these effects. These foods are especially rich in polyphenols, being the most relevant in the MD hydroxytyrosol (HT) and their derivatives present in EVOO, which have demonstrated a wide array of biological activities. Here, we demonstrate that HT is able to reduce the inflammation induced by two different stimuli: lipopolysaccharide and α-synuclein. We also study the possible molecular mechanisms involved in the anti-inflammatory effect of HT, including the study of nuclear factor kappa B (NF-кB), mitogen-activated protein kinases (MAPKs), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and inflammasome. Our data support the use of HT to prevent the inflammation associated with PD and shed light into the relationship between MD and this neurological disorder.
The oral antidiabetic drug metformin is known to exhibit anti-inflammatory properties through activation of AMP kinase, thus protecting various brain tissues as cortical neurons, for example. ...However, the effect of metformin on the substantia nigra (SN), the main structure affected in Parkinson's disease (PD), has not yet been studied in depth. Inflammation is a key feature of PD and it may play a central role in the neurodegeneration that takes place in this disorder. The aim of this work was to determine the effect of metformin on the microglial activation of the SN of rats using the animal model of PD based on the injection of the pro-inflammogen lipopolysaccharide (LPS).
and
experiments were conducted to study the activation of microglia at both the cellular and molecular levels. Our results indicate that metformin overall inhibits microglia activation measured by OX-6 (MHCII marker), IKKβ (pro-inflammatory marker) and arginase (anti-inflammatory marker) immunoreactivity. In addition, qPCR experiments reveal that metformin treatment minimizes the expression levels of several pro- and anti-inflammatory cytokines. Mechanistically, the drug decreases the phosphorylated forms of mitogen-activated protein kinases (MAPKs) as well as ROS generation through the inhibition of the NADPH oxidase enzyme. However, metformin treatment fails to protect the dopaminergic neurons of SN in response to intranigral LPS. These findings suggest that metformin could have both beneficial and harmful pharmacological effects and raise the question about the potential use of metformin for the prevention and treatment of PD.
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