Frontiers in Cellular Neuroscience最新文献

The persistence or emergence of long-term symptoms following resolution of primary SARS-CoV-2 infection is referred to as long COVID or post-acute sequelae of COVID-19 (PASC). PASC predominantly affects the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems. Among these, the central nervous system (CNS) is significantly impacted, leading to a spectrum of symptoms, including fatigue, headaches, brain fog, cognitive impairment, anosmia, hypogeusia, neuropsychiatric symptoms, and peripheral neuropathy (neuro-PASC). However, the risk factors and pathogenic mechanisms responsible for neuro-PASC remain unclear. This review hypothesis discusses the leading hypotheses regarding the pathophysiological mechanisms involved in long COVID/PASC, focusing on neuro-PASC. We propose vascular dysfunction mediated by activation of astrocytes and pericytes followed by blood-brain barrier (BBB) disruption as underlying pathophysiological mechanisms of neurological manifestations. Additionally, we provide insights into the role of spike protein at the blood-brain interface. Finally, we explore the potential pathogenic mechanisms initiated by the interaction between the spike protein and cellular receptors at the brain endothelial and tissue levels.

Multiple sclerosis (MS), a debilitating autoimmune disorder targeting the central nervous system (CNS), is marked by relentless demyelination and inflammation. Clinically, it presents in three distinct forms: relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). While disease-modifying therapies (DMTs) offer some relief to people with RRMS, treatment options for progressive MS (pMS) remain frustratingly inadequate. This gap highlights an urgent need for advanced disease modeling techniques to unravel the intricate pathology of pMS. Human induced pluripotent stem cell (iPSC) technologies and brain organoids are emerging as promising tools for disease modeling in both 2D and 3D in vitro environments. These innovative approaches enable the study of disease mechanisms that closely mimic human pathophysiology and offer new platforms for screening therapeutic compounds, surpassing the limitations of traditional animal models. However, deploying brain organoids in disease modeling presents challenges, especially in the context of non-monogenic disorders. This review delves into cutting-edge brain organoid techniques that hold the potential to revolutionize our understanding of pMS, offering a pathway to disentangle its underlying mechanisms and drive transformative discoveries.

Introduction: Recent work has revealed that clonal hematopoiesis (CH) is associated with a higher risk of numerous age-related diseases, including ischemic stroke, however little is known about whether it influences stroke outcome independent of its widespread effects on cardiovascular disease. Studies suggest that leukocytes carrying CH driver mutations have an enhanced inflammatory profile, which could conceivably exacerbate brain injury after a stroke.

Methods: Using a competitive bone marrow transplant model of Tet2-mediated CH, we tested the hypothesis that CH would lead to a poorer outcome after ischemic stroke by augmenting brain inflammation. Stroke was induced in mice by middle cerebral artery occlusion and neurological outcome was assessed at acute (24 h) and subacute (14 d) timepoints. Brains were collected at both time points for histological, immunofluorescence and gene expression assays.

Results: Unexpectedly, Tet2-mediated CH had no effect on acute stroke outcome but led to a reduction in neurological deficits during the subacute phase. This improved neurological outcome was associated with lower levels of brain inflammation as evidenced by lower transcript levels of various inflammatory molecules alongside reduced astrogliosis.

Discussion: These findings suggest that Tet2-mediated CH may have beneficial effects on outcome after stroke, contrasting with the conventional understanding of CH whereby leukocytes with driver mutations promote disease by exacerbating inflammation.

Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) are indispensable core techniques in cardiac surgery. Numerous studies have shown that cardiopulmonary bypass and deep hypothermic circulatory arrest are associated with the occurrence of neuroinflammation, accompanied by the activation of microglia. Microglia, as macrophages in the central nervous system, play an irreplaceable role in neuroinflammation. Current research on neuroinflammation induced by microglia activation mainly focuses on neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, neuropathic pain, acquired brain injury, and others. However, there is relatively limited research on microglia and neuroinflammation under conditions of cardiopulmonary bypass and deep hypothermic circulatory arrest. The close relationship between cardiopulmonary bypass, deep hypothermic circulatory arrest, and cardiac surgery underscores the importance of identifying targets for intervening in neuroinflammation through microglia. This could greatly benefit cardiac surgery patients during cardiopulmonary bypass and the perioperative period, significantly improving patient prognosis. This review article provides the first comprehensive discussion on the signaling pathways associated with neuroinflammation triggered by microglia activation, the impact of cardiopulmonary bypass on microglia, as well as the current status and advancements in cardiopulmonary bypass animal models. It provides new insights and methods for the treatment of neuroinflammation related to cardiopulmonary bypass and deep hypothermic circulatory arrest, holding significant importance for clinical treatment by cardiac surgeons, management strategies by cardiopulmonary bypass physicians, and the development of neurologically related medications.

Introduction: Abnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimer's disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD). Tau deposits primarily affect neurons, but evidence indicates that glial cells may also be affected and contribute distinctively to disease progression. Cells can respond to toxic insults by orchestrating global changes in posttranslational modifications of their proteome. Previous studies suggest that SUMOylation, a posttranslational modification consisting of conjugation of SUMO (Small ubiquitin-like modifier) to target proteins, was decreased in the hippocampus of AD patients and in animal model of AD compared with controls. This decrease in SUMOylation was correlated with increased Tau pathology and cognitive decline. Other studies have reported increased levels of SUMO in AD brains. The goal of our study was to evaluate whether SUMO conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant TauP301L, in neurons and in glial cells.

Methods: We used viral approaches to express mutant TauP301L and SUMO2 in the hippocampus of wild-type mice. We assessed Tau distribution by immunostaining and Tau aggregation by insolubility assays followed by western blotting. We assessed neuronal toxicity and performed cell count and shape descriptor analyses on astrocytes and microglial cells.

Results: We found that mutant TauP301L, when expressed exclusively in neurons, is toxic not only to neurons but also to glial cells, and that SUMO2 counteracts TauP301L toxicity in neurons as well as in glia.

Discussion: Our results uncover an endogenous neuroprotective mechanism, whereby SUMO2 conjugation reduces Tau neuropathology and protects against toxic effects of Tau in glial cells.

The locus coeruleus (LC) produces most of the brain's noradrenaline (NA). Among its many roles, NA is often said to be neuroprotective and important for brain upkeep. For this reason, loss of LC integrity is thought to impact brain volume and microstructure as well as plasticity broadly. LC dysfunction is also a suspected driver in the development of neurodegenerative diseases. Nevertheless, the impact of LC dysfunction on the gross structure and microstructure of normal brains is not well-studied. We employed high-field ex vivo magnetic resonance imaging (MRI) to investigate brain volumetrics and microstructure in control (CON) mice and mice with LC ablation (LCA) at two ages, representing the developing brain and the fully matured brain. These whole-brain methods are known to be capable of detecting subtle morphological changes and brain microstructural remodeling. We found mice behavior consistent with histologically confirmed LC ablation. However, MRI showed no difference between CON and LCA groups with regard to brain size, relative regional volumes, or regional microstructural indices. Our findings suggest that LC-NA is not needed for postnatal brain maturation and growth in mice. Nor is it required for maintenance in the normal adult mouse brain, as no atrophy or microstructural aberration is detected after weeks of LC dysfunction. This adds clarity to the often-encountered notion that LC-NA is important for brain "trophic support" as it shows that such effects are likely most relevant to mechanisms related to brain plasticity and neuroprotection in the (pre)diseased brain.

Müller cells are the most abundant glial cells in the mammalian retina. Their morphology and metabolism enable them to be in close contact and interact biochemically and physically with almost all retinal cell types, including neurons, pericytes, endothelial cells, and other glial cells, influencing their physiology by releasing bioactive molecules. Studies indicate that Müller glial cells are the primary source of angiogenic growth factor secretion in the neuroretina. Because of this, over the past decade, it has been postulated that Müller glial cells play a significant role in maintaining retinal vascular homeostasis, with potential implications in vasoproliferative retinopathies. This review aims to summarize the current understanding of the mechanisms by which Müller glial cells influence retinal angiogenesis in health and disease, with a particular emphasis on three of the retinopathies with the most significant impact on visual health worldwide: diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has profoundly impacted global health, affecting not only the immediate morbidity and mortality rates but also long-term health outcomes across various populations. Although the acute effects of COVID-19 on the respiratory system have initially been the primary focus, it is increasingly evident that the virus can have significant impacts on multiple physiological systems, including the nervous and immune systems. The pandemic has highlighted the complex interplay between viral infection, immune aging, and brain health, that can potentially accelerate neuroimmune aging and contribute to the persistence of long COVID conditions. By inducing chronic inflammation, immunosenescence, and neuroinflammation, COVID-19 may exacerbate the processes of neuroimmune aging, leading to increased risks of cognitive decline, neurodegenerative diseases, and impaired immune function. Key factors include chronic immune dysregulation, oxidative stress, neuroinflammation, and the disruption of cellular processes. These overlapping mechanisms between aging and COVID-19 illustrate how the virus can induce and accelerate aging-related processes, leading to an increased risk of neurodegenerative diseases and other age-related conditions. This mini-review examines key features and possible mechanisms of COVID-19-induced neuroimmune aging that may contribute to the persistence and severity of long COVID. Understanding these interactions is crucial for developing effective interventions. Anti-inflammatory therapies, neuroprotective agents, immunomodulatory treatments, and lifestyle interventions all hold potential for mitigating the long-term effects of the virus. By addressing these challenges, we can improve health outcomes and quality of life for millions affected by the pandemic.

Introduction and methods: Aiming to evaluate safety aspects of a recently proposed approach to target Alzheimer's disease, we mimicked a complex boron neutron capture therapy field using a mixed beam consisting of high- and low-linear energy transfer (LET) radiation, ²⁴¹Am alpha particles (α) and/or X-ray radiation respectively, in human microglial (HMC3) cells.

Results: Acute exposure to 2 Gy X-rays induced the strongest response in the formation of γH2AX foci 30 min post irradiation, while α- and mixed beam-induced damage (α:X-ray = 3:1) sustained longer. Fractionation of the same total dose (0.4 Gy daily) induced a similar number of γH2AX foci as after acute radiation, however, α- or mixed irradiation caused a higher expression of DNA damage response genes CDKN1A and MDM2 24 h after the last fraction, as well as a stronger decrease in cell viability and clonogenic survival compared to acute exposure. Phosphorylation of STING, followed by phosphorylation of NF-κB subunit p65, was rapidly induced (1 or 3 h, respectively) after the last fraction by all radiation qualities. This led to IL-1β secretion into the medium, strongly elevated expression of pro-inflammatory cytokine genes and enhanced phagocytosis after fractionated exposure to α- and mixed beam-irradiation compared to their acute counterparts 24 h post-irradiation. Nevertheless, all inflammatory changes were returning to basal levels or below 10-14 days post irradiation.

Discussion: In conclusion, we demonstrate strong transient pro-inflammatory induction by daily high-LET radiation in a microglia model, triggering phagocytosis which may aid in clearing amyloid beta, but importantly, from a safety perspective, without long-term alterations.