ASN NEURO最新文献

The circumventricular organs (CVOs) are unique areas within the central nervous system. They serve as a portal for the rest of the body and, as such, lack a blood-brain barrier. Microglia are the primary resident immune cells of the brain parenchyma. Within the CVOs, microglial cells find themselves continuously challenged and stimulated by local and systemic stimuli, even under steady-state conditions. Therefore, CVO microglia in their typical state often resemble the activated microglial forms found elsewhere in the brain as they are responding to pathological conditions or other stressors. In this review, I focus on the dynamics of CVO microglia, using the pineal gland as a specific CVO example. Data related to microglia heterogeneity in both homeostatic and unhealthy environments are presented and discussed, including those recently generated by using advanced single-cell and single-nucleus technology. Finally, perspectives in the CVO microglia field are also included.Summary StatementMicroglia in circumventricular organs (CVOs) continuously adapt to react differentially to the diverse challenges they face. Herein, I discuss microglia heterogeneity in CVOs, including pineal gland. Further studies are needed to better understand microglia dynamics in these unique brain areas. .

The high lipid content of the brain, coupled with its heavy oxygen dependence and relatively weak antioxidant system, makes it highly susceptible to oxidative DNA damage that contributes to neurodegeneration. This study is aimed at identifying specific ROS-responsive miRNAs that modulate the expression and activity of the DNA repair proteins in human astrocytes, which could serve as potential biomarkers and lead to the development of targeted therapeutic strategies for neurological diseases. Oxidative DNA damage was established after treatment of human astrocytes with 10μM sodium dichromate for 16 h. Comet assay analysis indicated a significant increase in oxidized guanine lesions. RT-qPCR and ELISA assays confirmed that sodium dichromate reduced the mRNA and protein expression levels of the human base-excision repair enzyme, 8-deoxyguanosine DNA glycosylase 1 (hOGG1). Small RNAseq data were generated on an Ion Torrent™ system and the differentially expressed miRNAs were identified using Partek Flow® software. The biologically significant miRNAs were selected using miRNet 2.0. Oxidative-stress-induced DNA damage was associated with a significant decrease in miRNA expression: 231 downregulated miRNAs and 2 upregulated miRNAs (p < 0.05; >2-fold). In addition to identifying multiple miRNA-mRNA pairs involved in DNA repair processes, this study uncovered a novel miRNA-mRNA pair interaction: miR-1248:OGG1. Inhibition of miR-1248 via the transfection of its inhibitor restored the expression levels of hOGG1. Therefore, targeting the identified microRNA candidates could ameliorate the nuclear DNA damage caused by the brain's exposure to mutagens, reduce the incidence and improve the treatment of cancer and neurodegenerative disorders.

Müller glial cells (MGCs), the main glial component of the retina, play an active role in retinal homeostasis during development and pathological processes. They strongly monitor retinal environment and, in response to retinal imbalance, activate neuroprotective mechanisms mainly characterized by the increase of glial fibrillary acidic protein (GFAP). Under these circumstances, if homeostasis is not reestablished, the retina can be severely injured and GFAP contributes to neuronal degeneration, as they occur in several proliferative retinopathies such as diabetic retinopathy, sickle cell retinopathy and retinopathy of prematurity. In addition, MGCs have an active participation in inflammatory responses releasing proinflammatory mediators and metalloproteinases to the extracellular space and vitreous cavity. MGCs are also involved in the retinal neovascularization and matrix extracellular remodeling during the proliferative stage of retinopathies. Interestingly, low-density lipoprotein receptor-related protein 1 (LRP1) and its ligand α₂-macroglobulin (α₂M) are highly expressed in MGCs and they have been established to participate in multiple cellular and molecular activities with relevance in retinopathies. However, the exact mechanism of regulation of retinal LRP1 in MGCs is still unclear. Thus, the active participation of MGCs and LRP1 in these diseases, strongly supports the potential interest of them for the design of novel therapeutic approaches. In this review, we discuss the role of LRP1 in the multiple MGCs activities involved in the development and progression of proliferative retinopathies, identifying opportunities in the field that beg further research in this topic area.Summary StatementMGCs and LRP1 are active players in injured retinas, participating in key features such as gliosis and neurotoxicity, neovascularization, inflammation, and glucose control homeostasis during the progression of ischemic diseases, such as proliferative retinopathies.

Depression is a common psychiatric comorbidity in patients with epilepsy, especially those with temporal lobe epilepsy (TLE). The aim of this study was to assess changes in high mobility group box protein 1 (HMGB1) expression in epileptic patients with and without comorbid depression. Sixty patients with drug-resistant TLE who underwent anterior temporal lobectomy were enrolled. Anterior hippocampal samples were collected after surgery and analyzed by immunofluorescence (n = 7/group). We also evaluated the expression of HMGB1 in TLE patients with hippocampal sclerosis and measured the level of plasma HMGB1 by enzyme-linked immunosorbent assay. The results showed that 28.3% of the patients (17/60) had comorbid depression. HMGB1 was ubiquitously expressed in all subregions of the anterior hippocampus. The ratio of HMGB1-immunoreactive neurons and astrocytes was significantly increased in both TLE patients with hippocampal sclerosis and TLE patients with comorbid depression compared to patients with TLE only. The ratio of cytoplasmic to nuclear HMGB1-positive neurons in the hippocampus was higher in depressed patients with TLE than in nondepressed patients, which suggested that more HMGB1 translocated from the nucleus to the cytoplasm in the depressed group. There was no significant difference in the plasma level of HMGB1 among patients with TLE alone, TLE with hippocampal sclerosis, and TLE with comorbid depression. The results of the study revealed that the translocation of HMGB1 from the nucleus to the cytoplasm in hippocampal neurons may play a previously unrecognized role in the initiation and amplification of epilepsy and comorbid depression. The direct targeting of neural HMGB1 is a promising approach for anti-inflammatory therapy.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration. Life expectancy and age of onset in MS patients have been rising over the last decades, and previous studies have shown that age affects disease progression. Therefore, age appears as one of the most important factors in accumulating disability in MS patients. Indeed, the degeneration of oligodendrocytes (OGDs) and OGD precursors (OPCs) increases with age, in association with increased inflammatory activity of astrocytes and microglia. Similarly, age-related neuronal changes such as mitochondrial alterations, an increase in oxidative stress, and disrupted paranodal junctions can impact myelin integrity. Conversely, once myelination is complete, the long-term integrity of axons depends on OGD supply of energy. These alterations determine pathological myelin changes consisting of myelin outfolding, splitting, and accumulation of multilamellar fragments. Overall, these data demonstrate that old mature OGDs lose their ability to produce and maintain healthy myelin over time, to induce de novo myelination, and to remodel pre-existing myelinated axons that contribute to neural plasticity in the CNS. Furthermore, as observed in other tissues, aging induces a general decline in regenerative processes and, not surprisingly, progressively hinders remyelination in MS. In this context, this review will provide an overview of the current knowledge of age-related changes occurring in cells of the oligodendroglial lineage and how they impact myelin synthesis, axonal degeneration, and remyelination efficiency.

The retina of vertebrates is responsible for capturing light through visual (cones and rods) and non-visual photoreceptors (intrinsically photosensitive retinal ganglion cells and horizontal cells) triggering a number of essential activities associated to image- and non-image forming functions (photic entrainment of daily rhythms, pupillary light reflexes, pineal melatonin inhibition, among others). Although the retina contains diverse types of neuronal based-photoreceptors cells, originally classified as ciliary- or rhabdomeric-like types, in recent years, it has been shown that the major glial cell type of the retina, the Müller glial cells (MC), express blue photopigments as Opn3 (encephalopsin) and Opn5 (neuropsin) and display light responses associated to intracellular Ca2 + mobilization. These findings strongly propose MC as novel retinal photodetectors (Rios et al., 2019). Herein, we further investigated the intrinsic light responses of primary cultures of MC from embryonic chicken retinas specially focused on Ca2 + mobilization by fluorescence imaging and the identity of the internal Ca2 + stores responsible for blue light responses. Results clearly demonstrated that light responses were specific to blue light of long time exposure, and that the main Ca2 + reservoir to trigger downstream responses came from intracellular stores localized in the endoplasmic reticulum These observations bring more complexity to the intrinsic photosensitivity of retinal cells, particularly with regard to the detection of light in the blue range of visible spectra, and add novel functions to glial cells cooperating with other photoreceptors to detect and integrate ambient light in the retinal circuit and participate in cell to cell communication.Summary statement:Non-neuronal cells in the vertebrate retina, Muller glial cells, express non-canonical photopigments and sense blue light causing calcium release from intracellular stores strongly suggesting a novel intrinsic photosensitivity and new regulatory events mediating light-driven processes with yet unknown physiological implications.

A major limitation of mechanistic studies in aging brains is the lack of routine methods to robustly visualize and discriminate the cellular distribution of tissue antigens using fluorescent immunohistochemical multi-labeling techniques. Although such approaches are routine in non-aging brains, they are not consistently feasible in the aging brain due to the progressive accumulation of autofluorescent pigments, particularly lipofuscin, which strongly excite and emit over a broad spectral range. Consequently, aging research has relied upon colorimetric antibody techniques, where discrimination of tissue antigens is often challenging. We report the application of a simple, reproducible, and affordable protocol using multispectral light-emitting diodes (mLEDs) exposure for the reduction/elimination of lipofuscin autofluorescence (LAF) in aging brain tissue from humans, non-human primates, and mice. The mLEDs lamp has a broad spectral range that spans from the UV to infrared range and includes spectra in the violet/blue and orange/red. After photo quenching, the LAF level was markedly reduced when the tissue background fluorescence before and after mLEDs exposure was compared (p < 0.0001) across the spectral range. LAF elimination was estimated at 95 ± 1%. This approach permitted robust specific fluorescent immunohistochemical co-visualization of commonly studied antigens in aging brains. We also successfully applied this method to specifically visualize CD44 variant expression in aging human cerebral white matter using RNAscope fluorescent in-situ hybridization. Photo quenching provides an attractive means to accelerate progress in aging research by increasing the number of molecules that can be topologically discriminated by fluorescence detection in brain tissue from normative or pathological aging.