| 1. |
- Alonso-Bellido, Isabel M., et al.
(författare)
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The Other Side of SARS-CoV-2 Infection : Neurological Sequelae in Patients
- 2021
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13
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Forskningsöversikt (refereegranskat)abstract
- The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the globe causing coronavirus disease 2019 (COVID-19). Because it affects the respiratory system, common symptoms are cough and breathing difficulties with fever and fatigue. Also, some cases progress to acute respiratory distress syndrome (ARDS). The acute phase of COVID-19 has been also related to nervous system symptoms, including loss of taste and smell as well as encephalitis and cerebrovascular disorders. However, it remains unclear if neurological complications are due to the direct viral infection of the nervous system, or they appear as a consequence of the immune reaction against the virus in patients who presented pre-existing deficits or had a certain detrimental immune response. Importantly, the medium and long-term consequences of the infection by SARS-CoV-2 in the nervous system remain at present unknown. This review article aims to give an overview of the current neurological symptoms associated with COVID-19, as well as attempting to provide an insight beyond the acute affectation.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- Bachiller, Sara, et al.
(författare)
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The Ubiquitin Proteasome System in Neuromuscular Disorders : Moving Beyond Movement
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 21:17
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Forskningsöversikt (refereegranskat)abstract
- Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases. The ubiquitin-proteasome system (UPS) plays a fundamental role in maintaining protein homeostasis, being involved in protein degradation, among other cellular functions. Through a cascade of enzymatic reactions, proteins are ubiquitinated, tagged, and translocated to the proteasome to be degraded. Within the ubiquitin system, we can find three main groups of enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin-protein ligases). Only the ubiquitinated proteins with specific chain linkages (such as K48) will be degraded by the UPS. In this review, we describe the relevance of this system in NMDs, summarizing the UPS proteins that have been involved in pathological conditions and neuromuscular disorders, such as Spinal Muscular Atrophy (SMA), Charcot-Marie-Tooth disease (CMT), or Duchenne Muscular Dystrophy (DMD), among others. A better knowledge of the processes involved in the maintenance of proteostasis may pave the way for future progress in neuromuscular disorder studies and treatments.
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| 5. |
- Manouchehrian, Oscar, et al.
(författare)
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Acute systemic LPS-exposure impairs perivascular CSF distribution in mice
- 2021
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The exchange of cerebrospinal (CSF) and interstitial fluid is believed to be vital for waste clearance in the brain. The sleep-dependent glymphatic system, which is comprised of perivascular flow of CSF and is largely dependent on arterial pulsatility and astrocytic aquaporin-4 (AQP4) expression, facilitates much of this brain clearance. During the last decade, several observations have indicated that impaired glymphatic function goes hand in hand with neurodegenerative diseases. Since pathologies of the brain carry inflammatory components, we wanted to know how acute inflammation, e.g., with lipopolysaccharide (LPS) injections, would affect the glymphatic system. In this study, we aim to measure the effect of LPS on perivascular CSF distribution as a measure of glymphatic function.METHODS: Three hours after injection of LPS (1 mg/kg i.p.), C57bl/6 mice were (1) imaged for two CSF tracers, injected into cisterna magna, (2) transcardially perfused with buffer, or (3) used for physiological readouts. Tracer flow was imaged using a low magnification microscope on fixed brains, as well as using vibratome-cut slices for measuring tracer penetration in the brain. Cytokines, glial, and BBB-permeability markers were measured with ELISAs, Western blots, and immunohistochemistry. Cerebral blood flow was approximated using laser Doppler flowmetry, respiration and heart rate with a surgical monitor, and AQP4-polarization was quantified using confocal microscopy of immunolabeled brain sections.RESULTS: LPS-injections significantly lowered perivascular CSF tracer flow and penetration into the parenchyma. No differences in AQP4 polarization, cytokines, astroglial and BBB markers, cerebral blood flow, or respiration were detected in LPS-injected mice, although LPS did elevate cortical Iba1+ area and heart rate.CONCLUSIONS: This study reports another physiological response after acute exposure to the bacterial endotoxin LPS, namely the statistically significant decrease in perivascular distribution of CSF. These observations may benefit our understanding of the role of systemic inflammation in brain clearance.
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| 6. |
- Paulus, Agnes, et al.
(författare)
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Amyloid Structural Changes Studied by Infrared Microspectroscopy in Bigenic Cellular Models of Alzheimer’s Disease
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 22:7
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease affects millions of lives worldwide. This terminal disease is characterized by the formation of amyloid aggregates, so-called amyloid oligomers. These oligomers are composed of β-sheet structures, which are believed to be neurotoxic. However, the actual secondary structure that contributes most to neurotoxicity remains unknown. This lack of knowledge is due to the challenging nature of characterizing the secondary structure of amyloids in cells. To overcome this and investigate the molecular changes in proteins directly in cells, we used synchrotron-based infrared microspectroscopy, a label-free and non-destructive technique available for in situ molecular imaging, to detect structural changes in proteins and lipids. Specifically, we evaluated the formation of β-sheet structures in different monogenic and bigenic cellular models of Alzheimer’s disease that we generated for this study. We report on the possibility to discern different amyloid signatures directly in cells using infrared microspectroscopy and demonstrate that bigenic (amyloid-β, α-synuclein) and (amyloid-β, Tau) neuron-like cells display changes in β-sheet load. Altogether, our findings support the notion that different molecular mechanisms of amyloid aggregation, as opposed to a common mechanism, are triggered by the specific cellular environment and, therefore, that various mechanisms lead to the development of Alzheimer’s disease.
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| 7. |
- Svensson, Martina, et al.
(författare)
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The effect of electroconvulsive therapy on neuroinflammation, behavior and amyloid plaques in the 5xFAD mouse model of Alzheimer's disease
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Microglial cells are affected in Alzheimer's disease (AD) and interact with amyloid-beta (Aβ) plaques. Apart from memory loss, depression is common in patients with AD. Electroconvulsive therapy (ECT) is an anti-depressive treatment that may stimulate microglia, induce neuroinflammation and alter the levels of soluble Aβ, but the effects of ECT on microglia and Aβ aggregation in AD are not known. We investigated the short- and long-term effects of ECT on neuroinflammation and Aβ accumulation. 5xFAD mice received either electroconvulsive stimulation (ECS n = 26) or sham treatment (n = 25) for 3 weeks. Microglia and Aβ were analyzed in samples collected 24 h, 5 weeks, or 9 weeks after the last treatment. Aβ plaques and microglia were quantified using immunohistochemistry. The concentration of soluble Aβ and cytokines was quantified using ELISA and levels of Aβ aggregates were measured with Western Blot. Microglial phagocytosis of Aβ in the hippocampus was evaluated by flow cytometry in Methoxy-X04 injected mice 24 h following the last ECS treatment. Y-maze and Elevated plus maze were performed to study behavior after 5 weeks. We could not detect any significant short- or long-term effects of ECS on Aβ pathology or neuroinflammation, but ECS reduced abnormal behavior in the Elevated Plus maze.
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| 8. |
- Szepesi, Zsuzsanna, et al.
(författare)
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Bidirectional Microglia–Neuron Communication in Health and Disease
- 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 are ramified cells that exhibit highly motile processes, which continuously survey the brain parenchyma and react to any insult to the CNS homeostasis. Although microglia have long been recognized as a crucial player in generating and maintaining inflammatory responses in the CNS, now it has become clear, that their function are much more diverse, particularly in the healthy brain. The innate immune response and phagocytosis represent only a little segment of microglia functional repertoire that also includes maintenance of biochemical homeostasis, neuronal circuit maturation during development and experience-dependent remodeling of neuronal circuits in the adult brain. Being equipped by numerous receptors and cell surface molecules microglia can perform bidirectional interactions with other cell types in the CNS. There is accumulating evidence showing that neurons inform microglia about their status and thus are capable of controlling microglial activation and motility while microglia also modulate neuronal activities. This review addresses the topic: how microglia communicate with other cell types in the brain, including fractalkine signaling, secreted soluble factors and extracellular vesicles. We summarize the current state of knowledge of physiological role and function of microglia during brain development and in the mature brain and further highlight microglial contribution to brain pathologies such as Alzheimer’s and Parkinson’s disease, brain ischemia, traumatic brain injury, brain tumor as well as neuropsychiatric diseases (depression, bipolar disorder, and schizophrenia).
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| 9. |
- Yang, Yiyi, et al.
(författare)
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LPS priming before plaque deposition impedes microglial activation and restrains Aβ pathology in the 5xFAD mouse model of Alzheimer's disease
- 2023
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Ingår i: Brain, Behavior, and Immunity. - 0889-1591. ; 113, s. 228-247
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Tidskriftsartikel (refereegranskat)abstract
- Microglia have an innate immunity memory (IIM) with divergent functions in different animal models of neurodegenerative diseases, including Alzheimer's disease (AD). AD is characterized by chronic neuroinflammation, neurodegeneration, tau tangles and β-amyloid (Aβ) deposition. Systemic inflammation has been implicated in contributing to the progression of AD. Multiple reports have demonstrated unique microglial signatures in AD mouse models and patients. However, the proteomic profiles of microglia modified by IIM have not been well-documented in an AD model. Therefore, in the present study, we investigate whether lipopolysaccharide (LPS)-induced IIM in the pre-clinical stage of AD alters the microglial responses and shapes the neuropathology. We accomplished this by priming 5xFAD and wild-type (WT) mice with an LPS injection at 6 weeks (before the robust development of plaques). 140 days later, we evaluated microglial morphology, activation, the microglial barrier around Aβ, and Aβ deposition in both 5xFAD primed and unprimed mice. Priming induced decreased soma size of microglia and reduced colocalization of PSD95 and Synaptophysin in the retrosplenial cortex. Priming appeared to increase phagocytosis of Aβ, resulting in fewer Thioflavin S+ Aβ fibrils in the dentate gyrus. RIPA-soluble Aβ 40 and 42 were significantly reduced in Primed-5xFAD mice leading to a smaller size of MOAB2+ Aβ plaques in the prefrontal cortex. We also found that Aβ-associated microglia in the Primed-5xFAD mice were less activated and fewer in number. After priming, we also observed improved memory performance in 5xFAD. To further elucidate the molecular mechanism underlying these changes, we performed quantitative proteomic analysis of microglia and bone marrow monocytes. A specific pattern in the microglial proteome was revealed in primed 5xFAD mice. These results suggest that the imprint signatures of primed microglia display a distinctive phenotype and highlight the potential for a beneficial adaption of microglia when intervention occurs in the pre-clinical stage of AD.
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