| 1. |
- Arroyo-García, Luis Enrique, et al.
(författare)
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Targeting galectin-3 to counteract spike-phase uncoupling of fast-spiking interneurons to gamma oscillations in Alzheimer’s disease
- 2023
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Ingår i: Translational Neurodegeneration. - : Springer Science and Business Media LLC. - 2047-9158. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer’s disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin-3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown. Methods: Here, we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo (20–80 Hz) by performing electrophysiological recordings in the hippocampal CA3 area of wild-type (WT) mice and of the 5×FAD mouse model of AD. In addition, the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes, and amyloid-β (Aβ) plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout (KO). Results: Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner, which was accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSNs) and pyramidal cells. We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevented Aβ42-induced degradation of gamma oscillations. Furthermore, the 5×FAD mice lacking gal3 (5×FAD-Gal3KO) exhibited WT-like gamma network dynamics and decreased Aβ plaque load. Conclusions: We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs, inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.
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| 2. |
- Espinosa-Oliva, Ana M., et al.
(författare)
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Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain
- 2024
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Ingår i: Neuropathology and Applied Neurobiology. - 0305-1846. ; 50:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Tayara, Khadija, et al.
(författare)
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Divergent effects of metformin on an inflammatory model of Parkinson’s disease
- 2018
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- 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). In vivo and in vitro 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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| 4. |
- Bachiller, Sara, et al.
(författare)
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Microglia in neurological diseases : A road map to brain-disease dependent-inflammatory response
- 2018
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 12
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Forskningsöversikt (refereegranskat)abstract
- Microglia represent a specialized population of macrophages-like cells in the central nervous system (CNS) considered immune sentinels that are capable of orchestrating a potent inflammatory response. Microglia are also involved in synaptic organization, trophic neuronal support during development, phagocytosis of apoptotic cells in the developing brain, myelin turnover, control of neuronal excitability, phagocytic debris removal as well as brain protection and repair. Microglial response is pathology dependent and affects to immune, metabolic. In this review, we will shed light on microglial activation depending on the disease context and the influence of factors such as aging, environment or cell-to-cell interaction.
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| 5. |
- Borrego-Ecija, Sergi, et al.
(författare)
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Galectin-3 is upregulated in frontotemporal dementia patients with subtype specificity
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260. ; 20:3, s. 1515-1526
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin-3 (Gal-3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal-3 levels in patients with FTD and assess its diagnostic potential. METHODS: We examined Gal-3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal-3 levels and other FTD markers were explored. RESULTS: Gal-3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal-3 levels were higher in cases with tau pathology than TAR-DNA Binding Protein 43 (TDP-43) pathology. Only MAPT mutation carriers displayed increased Gal-3 levels in CSF samples, which correlated with total tau and 14-3-3. DISCUSSION: Our findings underscore the potential of Gal-3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal-3 with neuronal injury markers.
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| 6. |
- Boza-Serrano, Antonio, et al.
(författare)
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Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 251-273
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.
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| 7. |
- Boza-serrano, Antonio, et al.
(författare)
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Galectin-3 is elevated in CSF and is associated with Aβ deposits and tau aggregates in brain tissue in Alzheimer’s disease
- 2022
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322.
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system(CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer’s disease(AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around Aβ plaques in both humanand mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance ofGal-3-associated infammation in AD, we aimed to investigate the Gal-3 infammatory response in the AD continuum. First,we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadiccases. We found that Gal-3 levels were signifcantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+microglial cells were associated with amyloid plaques of a larger size and more irregularshape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fuid (CSF) fromAD patients (n=119) compared to control individuals (n=36). CSF Gal-3 levels were elevated in AD patients comparedto controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin)than with amyloid-β. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered andassociated with other CSF neuroinfammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinfammatory component was more highly expressed in the CSF from amyloid-β positive (A+), CSF p-Tau181 positive (T+), andbiomarker neurodegeneration positive/negative (N+/−) (A+T+N+/−) groups compared to the A+T−N− group. Overall,Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential targetfor disease-modifying therapies involving the neuroinfammatory response.
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| 8. |
- Boza-Serrano, Antonio, et al.
(författare)
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Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer's disease mouse model 5xFAD
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common form of dementia characterized by the formation of amyloid plaques (Aβ). Over the last decade, the important role of the innate immune system for the disease development has been established. Chronic activation of microglial cells creates a proinflammatory environment, which is believed to be central for the development of the disease as well as its progression. We used the AD mouse model 5xFAD to investigate if inflammatory alterations are present in microglial cells before plaque deposition. We applied mass spectrometry and bioinformation analysis to elucidate early microglial alterations. Interestingly, we found the cytokines IL1β and IL10 to be elevated in the 5xFAD brain after the formation of Aβ plaque at 10 weeks only. Using mass spectrometry analysis of microglial cells with bioinformation analysis, we found JAK/STAT, p38 MAPK and Interleukin pathways affected in microglial cells before plaque deposition at 6 weeks. At 10 weeks, GO analysis showed affected pathways related to interferon-gamma regulation and MAPK pathways. Our study points toward early inflammatory changes in microglial cells even before the accumulation of Aβ.
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| 9. |
- Boza Serrano, Antonio
(författare)
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Microglial cells in Neurodegenerative Diseases. The Role of Galectin-3
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today, dementia such as, Alzheimer’s disease (AD), vascular diseases and motor neurodegenerative diseases, such as Parkinson’s disease (PD), represent a major public health problem. For instance, PD affect to more than 10 million people worldwide and almost 50 million people are affected by dementia. In fact, every year 9,9 millions new patients are diagnosed. Dementia is one of the major causes of disability among elderly people. The mechanisms affecting the disease progression for PD and AD share some common mechanism, such as the immune responses in the neural tissue. The immune system plays a major role in restoring the balance in our organism after injury and is divided in innate and adaptive immunity. The innate immune response is considered the first mechanism responding to the disease stimulus. The activation of the innate immune response can be triggered by different factors and elicit the activation of several cell types. Among the main cell types involved in the innate immune response, we find: microglial cells, astrocytes and oligodendrocytes. Following the innate immune action, the adaptive immune system is activated and B and T cells are recruited by antigen presenting cells to act on the response. The main task of the inflammatory response is to restore the tissue homeostasis after insult. The nature of the insult can vary, going from pathogens to tissue damage. To resolve the injury and restore the balance in the organism, these cells types can secrete a wide array of molecules, such as pro and anti-inflammatory molecules, growth factors and chemokines, all of them involved in the regulation of the innate immune response. The main cell type involved in the inflammatory response in the brain are microglial cells. They are considered the ”macrophages of the brain”. Microglial cells can develop different functions such as: phagocytosis, synaptic remodeling or opsonization. Hence, microglial cell activation is essential for the well function of the brain in disease and healthy brain. One of the main receptors involved in microglial activation are the Toll like receptors (TLR’s). These receptors can recognize, and be activated, by different molecules derived from injured/damages tissue or pathogen derived molecules. Between the different TLR’s, TLR4 is one of the most important due to its capacity to sense bacteria-derived molecules triggering the immune response. Our working hypothesis is focused on the role of the inflammatory response in neurodegenerative diseases with special attention on galectin-3 in the neurodegenerative diseases such as AD and PD. Galectin-3 is a molecule mainly released by microglial cells and involved in different functions including: phagocytosis, microglial activation and cell proliferation.In the present work, we describe for the first time galectin-3 acting as an endogenous ligand for TLR4 driving the microglial activation towards to a proinflammatory profile. Moreover, the lack of galectin-3 profoundly reduces the microglial activation that might affects to the progression of PD and AD. Furthermore, in our work we found galectin-3 acting as a Triggering Receptor in Myeloid Cells 2 (TREM2) ligand. TREM2 is the main innate immune-related risk factor in Alzheimer’s disease and it is involved in microglial activation, phagocytosis and plaque deposition in Alzheimer disease. Moreover, human TREM2 mutations, such as R47H, are related to a higher susceptibility to developed AD. Despite our efforts, further experiments will be necessary to fully elucidate the role of galectin-3 and its interaction with TREM2 in AD. Despite the before mentioned, when the inflammatory response start is not well known. In our research line, we aimed to study if the inflammatory response is already present before the typical signs of Alzheimer disease pathology appears. To that aim, we studied the microglial proteomic profile in microglial cells before and after the plaque deposits. We used a specific AD mouse model and we discovered an altered innate immune response already present before the plaque deposition.In summary, during my work, we have been able to identify an inflammatory role of galectin-3 in PD and AD, with special attention on the role of galectin-3 in the inflammatory response in relation with TLR4 and TREM2 signaling. Furthermore, we evaluated the proteomic profile of microglial cells isolated from AD mouse model before and after the amyloid beta plaque deposits and we found important inflammatory pathways and innate immune proteins altered even before the deposition of the first plaques.We hope our findings will be further investigated and hopefully be useful to find new potential therapeutic targets and elucidate inflammatory-related mechanisms in neurodegenerative diseases.
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| 10. |
- Boza-Serrano, Antonio, et al.
(författare)
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The role of Galectin-3 in α-synuclein-induced microglial activation
- 2014
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2
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Forskningsöversikt (refereegranskat)abstract
- Background: Parkinson's disease (PD) is the most prevalent neurodegenerative motor disorder. The neuropathology is characterized by intraneuronal protein aggregates of α-synuclein and progressive degeneration of dopaminergic neurons within the substantia nigra. Previous studies have shown that extracellular α-synuclein aggregates can activate microglial cells, induce inflammation and contribute to the neurodegenerative process in PD. However, the signaling pathways involved in α-synuclein-mediated microglia activation are poorly understood. Galectin-3 is a member of a carbohydrate-binding protein family involved in cell activation and inflammation. Therefore, we investigated whether galectin-3 is involved in the microglia activation triggered by α-synuclein. Results: We cultured microglial (BV2) cells and induced cell activation by addition of exogenous α-synuclein monomers or aggregates to the cell culture medium. This treatment induced a significant increase in the levels of proinflammatory mediators including the inducible Nitric Oxide Synthase (iNOS), interleukin 1 Beta (IL-1β) and Interleukin-12 (IL-12). We then reduced the levels of galectin-3 expression using siRNA or pharmacologically targeting galectin-3 activity using bis-(3-deoxy-3-(3-fluorophenyl-1H-1,2,3-triazol-1-yl)-β-D-galactopyranosyl)-sulfane. Both approaches led to a significant reduction in the observed inflammatory response induced by α-synuclein. We confirmed these findings using primary microglial cells obtained from wild-type and galectin-3 null mutant mice. Finally, we performed injections of α-synuclein in the olfactory bulb of wild type mice and observed that some of the α-synuclein was taken up by activated microglia that were immunopositive for galectin-3. Conclusions: We show that α-synuclein aggregates induce microglial activation and demonstrate for the first time that galectin-3 plays a significant role in microglia activation induced by α-synuclein. These results suggest that genetic down-regulation or pharmacological inhibition of galectin-3 might constitute a novel therapeutic target in PD and other synucleinopathies.
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