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McInvale JJ, Kuper LC, Li E, Bonanno J, Lorman D, Gumenick R, Vincenti SL, Newman LA. Estradiol effects on astrocytic aquaporin 4 and glutamate transporter 1 expression contribute to shifts in brain dynamics supporting spatial working memory. Behav Brain Res 2025; 487:115578. [PMID: 40199402 DOI: 10.1016/j.bbr.2025.115578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/04/2025] [Accepted: 04/04/2025] [Indexed: 04/10/2025]
Abstract
Estrogenic effects on astrocytes improve glutamate recycling and water homeostasis for neuroprotection in pathology. Estrogens also enhance spatial learning and memory. The current study looked at the effect of 17β-estradiol (E2) on astrocytic glutamate transporter 1 (GLT-1) and aquaporin 4 (AQP4) in the prelimbic cortex (PrL) and dorsal hippocampus (dHC), areas active in spatial (allocentric) working memory in comparison to dorsolateral striatum (dlStr) which is involved in response or egocentric learning. Ovariectomized, female, Long Evans rats received 0, 4.5 µg/kg, or 45 µg/kg of E2 in a sesame oil vehicle 24 and 48 h prior to a delayed spontaneous alternation task (dSA). In line with previous research dSA performance significantly improved with administration of E2 as compared to sesame oil vehicle. AQP4 and GLT-1 levels were brain area specific and E2 enhanced AQP4 and GLT-1 in brain areas associated with spatial working memory (PrL and dHC) as compared to dlStr. Additionally, AQP4 was found to have the highest density in the unmyelinated axon rich hilus while GLT-1 showed the highest density in the synaptically dense molecular layer. However, AQP4 density in the stratum radiatum was similar to the hilus after dSA, potentially supporting dynamic changes in AQP4 response to natural cognitive activity. Hilar and prelimbic AQP4 area stained was also negatively correlated with performance on the dSA, which supports the theory of increased polarity of AQP4 with healthy cognitive function. These data suggest astrocytic water and glutamate homeostasis shift with high levels of estrogens to support spatial strategies.
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Affiliation(s)
- Julie J McInvale
- Department of Psychological Science, Neuroscience and Behavior Program, Vassar College, Poughkeepsie, NY, USA
| | - Louisa C Kuper
- Department of Psychological Science, Neuroscience and Behavior Program, Vassar College, Poughkeepsie, NY, USA
| | - Evelyn Li
- Department of Psychological Science, Neuroscience and Behavior Program, Vassar College, Poughkeepsie, NY, USA
| | - James Bonanno
- Department of Psychological Science, Neuroscience and Behavior Program, Vassar College, Poughkeepsie, NY, USA
| | - Daniella Lorman
- Department of Psychological Science, Neuroscience and Behavior Program, Vassar College, Poughkeepsie, NY, USA
| | - Ruby Gumenick
- Department of Psychological Science, Neuroscience and Behavior Program, Vassar College, Poughkeepsie, NY, USA
| | - Sydney L Vincenti
- Department of Psychological Science, Neuroscience and Behavior Program, Vassar College, Poughkeepsie, NY, USA
| | - Lori A Newman
- Department of Psychological Science, Neuroscience and Behavior Program, Vassar College, Poughkeepsie, NY, USA.
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Ponce-Lopez T. Peripheral Inflammation and Insulin Resistance: Their Impact on Blood-Brain Barrier Integrity and Glia Activation in Alzheimer's Disease. Int J Mol Sci 2025; 26:4209. [PMID: 40362446 PMCID: PMC12072112 DOI: 10.3390/ijms26094209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood-brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology.
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Affiliation(s)
- Teresa Ponce-Lopez
- Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico
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Cruz-Sese J, Mirón-Alcala M, Alfonso-Triguero M, Olalde J, Ruiz L, Galbis-Gramage N, Cortes L, Escobar L, Preman P, Snellinx A, Saito T, Saido TC, Saiz-Aúz L, Rábano-Gutiérrez A, Tcw J, Goate A, Strooper BD, Alberdi E, Arranz AM. Divergent Effects of APOE3 and APOE4 Human Astrocytes on Key Alzheimer's Disease Hallmarks in Chimeric Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.28.635271. [PMID: 39975251 PMCID: PMC11838330 DOI: 10.1101/2025.01.28.635271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Despite strong evidence supporting that both astrocytes and apolipoprotein E (APOE) play crucial roles in the pathogenesis and progression of Alzheimer's disease (AD), the impact of astrocytes carrying different APOE variants on key AD pathological hallmarks remains largely unknown. To explore such effects in a human relevant context, we generated a chimeric model of AD. We transplanted isogenic APOE3 or APOE4 human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains of AD model mice. We show that at five to six months after transplantation, transplanted cells have differentiated into mature astrocytes (h-astrocytes) that often integrate in upper layers of one cortical hemisphere. APOE3 and APOE4 h-astrocytes differentially express and secrete the APOE protein, which binds to Aβ plaques with an isoform-dependent affinity. Remarkably, APOE3 h-astrocytes ameliorate Aβ pathology, Tau pathology and neuritic dystrophy. In contrast, APOE4 h-astrocytes aggravate these AD processes. Moreover, APOE3 and APOE4 h-astrocytes modulate microglia responses to Aβ pathology in opposite ways. APOE4 h-astrocytes enhance microglia clustering around Aβ plaques and exacerbate DAM state whereas APOE3 h-astrocytes reduce microglia clustering and induce a more homeostatic state on plaque-associated microglia. These findings highlight a critical contribution of h-astrocytes not only to Aβ pathology but also to other key AD hallmarks in chimeric mice. In addition, our findings reveal that h-astrocytes with different APOE variants and the different forms of APOE they secrete have a crucial role in AD progression.
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Zinsmaier AK, Nestler EJ, Dong Y. Astrocytic G Protein-Coupled Receptors in Drug Addiction. ENGINEERING (BEIJING, CHINA) 2025; 44:256-265. [PMID: 40109668 PMCID: PMC11922559 DOI: 10.1016/j.eng.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Understanding the cellular mechanisms of drug addiction remains a key task in current brain research. While neuron-based mechanisms have been extensively explored over the past three decades, recent evidence indicates a critical involvement of astrocytes, the main type of non-neuronal cells in the brain. In response to extracellular stimuli, astrocytes modulate the activity of neurons, synaptic transmission, and neural network properties, collectively influencing brain function. G protein-coupled receptors (GPCRs) expressed on astrocyte surfaces respond to neuron- and environment-derived ligands by activating or inhibiting astrocytic signaling, which in turn regulates adjacent neurons and their circuitry. In this review, we focus on the dopamine D1 receptors (D1R) and metabotropic glutamate receptor 5 (mGLUR5 or GRM5)-two GPCRs that have been critically implicated in the acquisition and maintenance of addiction-related behaviors. Positioned as an introductory-level review, this article briefly discusses astrocyte biology, outlines earlier discoveries about the role of astrocytes in substance-use disorders (SUDs), and provides detailed discussion about astrocytic D1Rs and mGLUR5s in regulating synapse and network functions in the nucleus accumbens (NAc)-a brain region that mediates addiction-related emotional and motivational responses. This review serves as a stepping stone for readers of Engineering to explore links between astrocytic GPCRs and drug addiction and other psychiatric disorders.
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Affiliation(s)
| | - Eric J Nestler
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA
| | - Yan Dong
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
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PĘkowska A, Verkhratsky A, Falcone C. Evolution of neuroglia: From worm to man. HANDBOOK OF CLINICAL NEUROLOGY 2025; 209:7-26. [PMID: 40122633 DOI: 10.1016/b978-0-443-19104-6.00004-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
Neuroglia are a highly diversified class of neural cells of ectodermal (astroglia; oligodendroglia, glia of the peripheral nervous system) and mesodermal (microglia) origin. Glial cells emerged at the earliest stages of the evolution of the nervous system, seemingly evolving several times in phylogeny. Initially, glial cells were associated with sensory organs, an arrangement conserved throughout the species from worms to humans. Enhanced complexity of the nervous system increased the need for homeostatic support, which, in turn, led to an increase in complexity, functional heterogeneity, and versatility of neuroglia. In the brain of primates, and especially in the brain of humans, astrocytes become exceedingly complex. Likewise, new types of astroglial cells involved in interlayer communication/integration have evolved in the primates evolutionary closer to humans. Increases in animal size and the density of interneuronal connections stimulated the development of the myelin sheath, which was critical for the evolution of the highly complex brains of humans. The innate brain tissue macrophages, the microglia, emerged in invertebrates such as leeches. Microglia conserved their transcriptomic, morphologic, and functional signatures throughout the animal kingdom.
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Affiliation(s)
- Aleksandra PĘkowska
- Dioscuri Centre for Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Bizkaia, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Carmen Falcone
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania; Neuroscience Department, SISSA, Trieste, Italy
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Ciani C, Falcone C. Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain. Front Cell Neurosci 2024; 18:1477753. [PMID: 39655243 PMCID: PMC11626530 DOI: 10.3389/fncel.2024.1477753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 11/05/2024] [Indexed: 12/12/2024] Open
Abstract
In the last years, science started to move toward a more glio-neurocentric view, in which astrocytes are hypothesized to be directly involved in cognitive functions. Indeed, astrocytes show a variety of shapes with species-specific characteristics, suggesting a specialization of roles during evolution. Interlaminar (ILA) and varicose-projection (VP-As) astrocytes show an anatomical organization that is different compared to the classical horizontal net typically formed by protoplasmic and fibrous astrocytes. ILAs show a modular architecture with the soma in the first cortical layer and processes toward the deep layers with species-specific length. VP-As reside in the deep layers of the cortex, are characterized by varicosities on the longest processes, and are individual-specific. These characteristics suggest roles that are more complex than what was theorized until now. Here, we recapitulate what we know so far from literature from the first time ILAs were described to the most recent discoveries, spanning from morphology description, hypothesis on the development to their features in diseases. For a complete glance on this topic, we included a final paragraph on which techniques and models were used to study ILAs and VP-As, and what new avenues may be opened thanks to more novel methods.
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Affiliation(s)
| | - Carmen Falcone
- Department of Neuroscience, International School for Advanced Studies (SISSA), Trieste, Italy
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Toledano A, Rodríguez-Casado A, Älvarez MI, Toledano-Díaz A. Alzheimer's Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models). Brain Sci 2024; 14:1101. [PMID: 39595866 PMCID: PMC11591712 DOI: 10.3390/brainsci14111101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical-pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. METHODS Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. RESULTS T2D and AD are not only "connected" by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central-or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. CONCLUSIONS Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process.
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Affiliation(s)
- Adolfo Toledano
- Instituto Cajal, CSIC, 28002 Madrid, Spain; (A.R.-C.); (M.I.Ä.)
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Kim S, Lee J, Koh IG, Ji J, Kim HJ, Kim E, Park J, Park JE, An JY. An integrative single-cell atlas for exploring the cellular and temporal specificity of genes related to neurological disorders during human brain development. Exp Mol Med 2024; 56:2271-2282. [PMID: 39363111 PMCID: PMC11541755 DOI: 10.1038/s12276-024-01328-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 10/05/2024] Open
Abstract
Single-cell technologies have enhanced comprehensive knowledge regarding the human brain by facilitating an extensive transcriptomic census across diverse brain regions. Nevertheless, understanding the cellular and temporal specificity of neurological disorders remains ambiguous due to developmental variations. To address this gap, we illustrated the dynamics of disorder risk gene expression under development by integrating multiple single-cell RNA sequencing datasets. We constructed a comprehensive single-cell atlas of the developing human brain, encompassing 393,060 single cells across diverse developmental stages. Temporal analysis revealed the distinct expression patterns of disorder risk genes, including those associated with autism, highlighting their temporal regulation in different neuronal and glial lineages. We identified distinct neuronal lineages that diverged across developmental stages, each exhibiting temporal-specific expression patterns of disorder-related genes. Lineages of nonneuronal cells determined by molecular profiles also showed temporal-specific expression, indicating a link between cellular maturation and the risk of disorder. Furthermore, we explored the regulatory mechanisms involved in early brain development, revealing enriched patterns of fetal cell types associated with neuronal disorders indicative of the prenatal stage's influence on disease determination. Our findings facilitate unbiased comparisons of cell type‒disorder associations and provide insight into dynamic alterations in risk genes during development, paving the way for a deeper understanding of neurological disorders.
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Affiliation(s)
- Seoyeon Kim
- Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea
- L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea
| | - Jihae Lee
- School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea
| | - In Gyeong Koh
- Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea
- L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea
| | - Jungeun Ji
- Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea
- L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea
| | - Hyun Jung Kim
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea
- Department of Anatomy, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Eunha Kim
- Department of Neuroscience, College of Medicine, Korea University, Seoul, Republic of Korea
- BK21 Graduate Program, Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Jihwan Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea
| | - Jong-Eun Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Joon-Yong An
- Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea.
- L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea.
- School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea.
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Chaudhary R, Rehman M, Agarwal V, Kumar A, Kaushik AS, Srivastava S, Srivastava S, Verma R, Rajinikanth PS, Mishra V. Terra incognita of glial cell dynamics in the etiology of leukodystrophies: Broadening disease and therapeutic perspectives. Life Sci 2024; 354:122953. [PMID: 39122110 DOI: 10.1016/j.lfs.2024.122953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 07/09/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
Neuroglial cells, also known as glia, are primarily characterized as auxiliary cells within the central nervous system (CNS). The recent findings have shed light on their significance in numerous physiological processes and their involvement in various neurological disorders. Leukodystrophies encompass an array of rare and hereditary neurodegenerative conditions that were initially characterized by the deficiency, aberration, or degradation of myelin sheath within CNS. The primary cellular populations that experience significant alterations are astrocytes, oligodendrocytes and microglia. These glial cells are either structurally or metabolically impaired due to inherent cellular dysfunction. Alternatively, they may fall victim to the accumulation of harmful by-products resulting from metabolic disturbances. In either situation, the possible replacement of glial cells through the utilization of implanted tissue or stem cell-derived human neural or glial progenitor cells hold great promise as a therapeutic strategy for both the restoration of structural integrity through remyelination and the amelioration of metabolic deficiencies. Various emerging treatment strategies like stem cell therapy, ex-vivo gene therapy, infusion of adeno-associated virus vectors, emerging RNA-based therapies as well as long-term therapies have demonstrated success in pre-clinical studies and show promise for rapid clinical translation. Here, we addressed various leukodystrophies in a comprehensive and detailed manner as well as provide prospective therapeutic interventions that are being considered for clinical trials. Further, we aim to emphasize the crucial role of different glial cells in the pathogenesis of leukodystrophies. By doing so, we hope to advance our understanding of the disease, elucidate underlying mechanisms, and facilitate the development of potential treatment interventions.
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Affiliation(s)
- Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Mujeeba Rehman
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Vipul Agarwal
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Anand Kumar
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Arjun Singh Kaushik
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Siddhi Srivastava
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Sukriti Srivastava
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Rajkumar Verma
- University of Connecticut School of Medicine, 200 Academic Way, Farmington, CT 06032, USA
| | - P S Rajinikanth
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Vikas Mishra
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India.
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Kharlamova A, Krivova Y, Proshchina A, Godovalova O, Otlyga D, Andreeva E, Shachina M, Grushetskaya E, Saveliev S. Spatial-temporal representation of the astroglial markers in the developing human cortex. Brain Struct Funct 2024:10.1007/s00429-024-02850-z. [PMID: 39153086 DOI: 10.1007/s00429-024-02850-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 08/07/2024] [Indexed: 08/19/2024]
Abstract
Specific spatiotemporal patterns of the normal glial differentiation during human brain development have not been thoroughly studied. Immunomorphological studies on postmortem material have remained a basic method for human neurodevelopmental studies so far. The main problem for the immunohistochemical research of astrogliogenesis is that now there are no universal astrocyte markers, that characterize the whole mature astrocyte population or precursors at each stage of development. To define the general course of astrogliogenesis in the developing human cortex, 25 fetal autopsy samples at the stages from eight postconceptional weeks to birth were collected for the immunomorphological analysis. Spatiotemporal immunoreactivity patterns with the panel of markers (ALDH1L1, GFAP, S100, SOX9, and Olig-2), related to glial differentiation were described and compared. The early S100 + cell population of ventral origin was described as well. This S100 + cell distribution deviated from the SOX9-immunoreactivity pattern and was similar to the Olig-2 one. In the given material the dorsal gliogenic wave was characterized by ALDH1L1-, GFAP-, and S100-immunoreactivity manifestation in the dorsal proliferative niche at the end of the early fetal period. The time point of dorsal astrogliogenesis was agreed upon not later than the 17 GW stage. ALDH1L1 + , GFAP + , S100 + , and SOX9 + cell expansion patterns from the ventricular and subventricular zones to the intermediate zone, subplate, and cortical plate were described at the end of early fetal, middle, and late fetal periods. The ALDH1L1-, GFAP-, and S100-immunoreactivity patterns were shown to be not completely identical.
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Affiliation(s)
- A Kharlamova
- Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery", Tsyurupy St., 3, Moscow, Russia, 117418.
| | - Yu Krivova
- Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery", Tsyurupy St., 3, Moscow, Russia, 117418
| | - A Proshchina
- Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery", Tsyurupy St., 3, Moscow, Russia, 117418
| | - O Godovalova
- Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery", Tsyurupy St., 3, Moscow, Russia, 117418
| | - D Otlyga
- Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery", Tsyurupy St., 3, Moscow, Russia, 117418
| | - E Andreeva
- Moscow Regional Research Institute of Obstetrics and Gynecology, Pokrovka St., 22A, Moscow, Russia, 101000
- FGBEU APE Russian Medical Academy Continuous Professional Education, Barrikadnaya St., 2/1, S.1, Moscow, Russia, 125993
| | - M Shachina
- Moscow Regional Research Institute of Obstetrics and Gynecology, Pokrovka St., 22A, Moscow, Russia, 101000
| | - E Grushetskaya
- Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery", Tsyurupy St., 3, Moscow, Russia, 117418
| | - S Saveliev
- Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery", Tsyurupy St., 3, Moscow, Russia, 117418
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11
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Paryani F, Kwon JS, Ng CW, Jakubiak K, Madden N, Ofori K, Tang A, Lu H, Xia S, Li J, Mahajan A, Davidson SM, Basile AO, McHugh C, Vonsattel JP, Hickman R, Zody MC, Housman DE, Goldman JE, Yoo AS, Menon V, Al-Dalahmah O. Multi-omic analysis of Huntington's disease reveals a compensatory astrocyte state. Nat Commun 2024; 15:6742. [PMID: 39112488 PMCID: PMC11306246 DOI: 10.1038/s41467-024-50626-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 07/09/2024] [Indexed: 08/10/2024] Open
Abstract
The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington's disease (HD) have not been fully defined. To explore the role of astrocytes in this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, and multiplexed immunofluorescence on HD and control post-mortem brains. We identified genes that correlated with CAG repeat length, which were enriched in astrocyte genes, and lipidomic signatures that implicated poly-unsaturated fatty acids in sensitizing neurons to cell death. Because astrocytes play essential roles in lipid metabolism, we explored the heterogeneity of astrocytic states in both protoplasmic and fibrous-like (CD44+) astrocytes. Significantly, one protoplasmic astrocyte state showed high levels of metallothioneins and was correlated with the selective vulnerability of distinct striatal neuronal populations. When modeled in vitro, this state improved the viability of HD-patient-derived spiny projection neurons. Our findings uncover key roles of astrocytic states in protecting against neurodegeneration in HD.
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Affiliation(s)
- Fahad Paryani
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Ji-Sun Kwon
- Department of Developmental Biology Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Christopher W Ng
- Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, USA
| | - Kelly Jakubiak
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Nacoya Madden
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Kenneth Ofori
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Alice Tang
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Hong Lu
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Shengnan Xia
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Juncheng Li
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Aayushi Mahajan
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Shawn M Davidson
- Northwestern Feinberg School of Medicine, Northwestern University, Evanston, IL, USA
| | | | | | - Jean Paul Vonsattel
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Richard Hickman
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | | | - David E Housman
- Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, USA
| | - James E Goldman
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA
| | - Andrew S Yoo
- Department of Developmental Biology Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Vilas Menon
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
| | - Osama Al-Dalahmah
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
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12
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Jeon J, Park YS, Kim SH, Kong E, Kim J, Yang JM, Lee JY, Kim YM, Kim IB, Kim P. Deciphering perivascular macrophages and microglia in the retinal ganglion cell layers. Front Cell Dev Biol 2024; 12:1368021. [PMID: 38596358 PMCID: PMC11002095 DOI: 10.3389/fcell.2024.1368021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/07/2024] [Indexed: 04/11/2024] Open
Abstract
Introduction: The classically defined two retinal microglia layers are distributed in inner and outer plexiform layers. Although there are some reports that retinal microglia are also superficially located around the ganglion cell layer (GCL) in contact with the vitreous, there has been a lack of detailed descriptions and not fully understood yet. Methods: We visualized the microglial layers by using CX3CR1-GFP (C57BL6) transgenic mice with both healthy and disease conditions including NaIO3-induced retinal degeneration models and IRBP-induced auto-immune uveitis models. Result: We found the GCL microglia has two subsets; peripheral (pph) microglia located on the retinal parenchyma and BAM (CNS Border Associated Macrophage) which have a special stretched phenotype only located on the surface of large retinal veins. First, in the pph microglia subset, but not in BAM, Galectin-3 and LYVE1 are focally expressed. However, LYVE1 is specifically expressed in the amoeboid or transition forms, except the typical dendritic morphology in the pph microglia. Second, BAM is tightly attached to the surface of the retinal veins and has similar morphology patterns in both the healthy and disease conditions. CD86+ BAM has a longer process which vertically passes the proximal retinal veins. Our data helps decipher the basic anatomy and pathophysiology of the retinal microglia in the GCL. Discussion: Our data helps decipher the basic anatomy and pathophysiology of the retinal microglia in the GCL.
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Affiliation(s)
- Jehwi Jeon
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- KI for Health Science and Technology (KIHST), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Yong Soo Park
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang-Hoon Kim
- Institute for Basic Science, Daejeon, Republic of Korea
| | - Eunji Kong
- Department of Neuroscience, Columbia University, New York, NY, United States
| | - Jay Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Jee Myung Yang
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joo Yong Lee
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - You-Me Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - In-Beom Kim
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pilhan Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- KI for Health Science and Technology (KIHST), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
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13
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Al-Dalahmah O, Sosunov AA, Sun Y, Liu Y, Madden N, Connolly ES, Troy CM, McKhann GM, Goldman JE. The Matrix Receptor CD44 Is Present in Astrocytes throughout the Human Central Nervous System and Accumulates in Hypoxia and Seizures. Cells 2024; 13:129. [PMID: 38247821 PMCID: PMC10814649 DOI: 10.3390/cells13020129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 11/20/2023] [Accepted: 12/22/2023] [Indexed: 01/23/2024] Open
Abstract
In the mammalian isocortex, CD44, a cell surface receptor for extracellular matrix molecules, is present in pial-based and fibrous astrocytes of white matter but not in protoplasmic astrocytes. In the hominid isocortex, CD44+ astrocytes comprise the subpial "interlaminar" astrocytes, sending long processes into the cortex. The hippocampus also contains similar astrocytes. We have examined all levels of the human central nervous system and found CD44+ astrocytes in every region. Astrocytes in white matter and astrocytes that interact with large blood vessels but not with capillaries in gray matter are CD44+, the latter extending long processes into the parenchyma. Motor neurons in the brainstem and spinal cord, such as oculomotor, facial, hypoglossal, and in the anterior horn of the spinal cord, are surrounded by CD44+ processes, contrasting with neurons in the cortex, basal ganglia, and thalamus. We found CD44+ processes that intercalate between ependymal cells to reach the ventricle. We also found CD44+ astrocytes in the molecular layer of the cerebellar cortex. Protoplasmic astrocytes, which do not normally contain CD44, acquire it in pathologies like hypoxia and seizures. The pervasive and inducible expression of CD44 in astrocytes is a novel finding that lays the foundations for functional studies into the significance of CD44 in health and disease.
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Affiliation(s)
- Osama Al-Dalahmah
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
| | - Alexander A. Sosunov
- Department of Neurosurgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA (E.S.C.)
| | - Yu Sun
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
| | - Yang Liu
- Department of Pathology, Albany Medical Center, Albany, NY 12208, USA
| | - Nacoya Madden
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
| | - E. Sander Connolly
- Department of Neurosurgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA (E.S.C.)
| | - Carol M. Troy
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
- The Taub Institute, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Guy M. McKhann
- Department of Neurosurgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA (E.S.C.)
| | - James E. Goldman
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
- The Taub Institute, Columbia University Irving Medical Center, New York, NY 10032, USA
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14
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Chameh HM, Falby M, Movahed M, Arbabi K, Rich S, Zhang L, Lefebvre J, Tripathy SJ, De Pittà M, Valiante TA. Distinctive biophysical features of human cell-types: insights from studies of neurosurgically resected brain tissue. Front Synaptic Neurosci 2023; 15:1250834. [PMID: 37860223 PMCID: PMC10584155 DOI: 10.3389/fnsyn.2023.1250834] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/21/2023] [Indexed: 10/21/2023] Open
Abstract
Electrophysiological characterization of live human tissue from epilepsy patients has been performed for many decades. Although initially these studies sought to understand the biophysical and synaptic changes associated with human epilepsy, recently, it has become the mainstay for exploring the distinctive biophysical and synaptic features of human cell-types. Both epochs of these human cellular electrophysiological explorations have faced criticism. Early studies revealed that cortical pyramidal neurons obtained from individuals with epilepsy appeared to function "normally" in comparison to neurons from non-epilepsy controls or neurons from other species and thus there was little to gain from the study of human neurons from epilepsy patients. On the other hand, contemporary studies are often questioned for the "normalcy" of the recorded neurons since they are derived from epilepsy patients. In this review, we discuss our current understanding of the distinct biophysical features of human cortical neurons and glia obtained from tissue removed from patients with epilepsy and tumors. We then explore the concept of within cell-type diversity and its loss (i.e., "neural homogenization"). We introduce neural homogenization to help reconcile the epileptogenicity of seemingly "normal" human cortical cells and circuits. We propose that there should be continued efforts to study cortical tissue from epilepsy patients in the quest to understand what makes human cell-types "human".
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Affiliation(s)
- Homeira Moradi Chameh
- Division of Clinical and Computational Neuroscience, Krembil Brain Institute, University Health Network (UHN), Toronto, ON, Canada
| | - Madeleine Falby
- Division of Clinical and Computational Neuroscience, Krembil Brain Institute, University Health Network (UHN), Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Mandana Movahed
- Division of Clinical and Computational Neuroscience, Krembil Brain Institute, University Health Network (UHN), Toronto, ON, Canada
| | - Keon Arbabi
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Scott Rich
- Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - Liang Zhang
- Division of Clinical and Computational Neuroscience, Krembil Brain Institute, University Health Network (UHN), Toronto, ON, Canada
| | - Jérémie Lefebvre
- Division of Clinical and Computational Neuroscience, Krembil Brain Institute, University Health Network (UHN), Toronto, ON, Canada
- Department of Biology, University of Ottawa, Ottawa, ON, Canada
- Department of Mathematics, University of Toronto, Toronto, ON, Canada
| | - Shreejoy J. Tripathy
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Maurizio De Pittà
- Division of Clinical and Computational Neuroscience, Krembil Brain Institute, University Health Network (UHN), Toronto, ON, Canada
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Basque Center for Applied Mathematics, Bilbao, Spain
- Faculty of Medicine, University of the Basque Country, Leioa, Spain
| | - Taufik A. Valiante
- Division of Clinical and Computational Neuroscience, Krembil Brain Institute, University Health Network (UHN), Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
- Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada
- Max Planck-University of Toronto Center for Neural Science and Technology, University of Toronto, Toronto, ON, Canada
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15
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Li J, Jaiswal MK, Chien JF, Kozlenkov A, Jung J, Zhou P, Gardashli M, Pregent LJ, Engelberg-Cook E, Dickson DW, Belzil VV, Mukamel EA, Dracheva S. Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation. Nat Commun 2023; 14:5714. [PMID: 37714849 PMCID: PMC10504300 DOI: 10.1038/s41467-023-41033-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 08/21/2023] [Indexed: 09/17/2023] Open
Abstract
A repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we investigate single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem motor and frontal cortices from C9-ALS, C9-FTD, and control donors. C9-ALS donors present pervasive alterations of gene expression with concordant changes in chromatin accessibility and histone modifications. The greatest alterations occur in upper and deep layer excitatory neurons, as well as in astrocytes. In neurons, the changes imply an increase in proteostasis, metabolism, and protein expression pathways, alongside a decrease in neuronal function. In astrocytes, the alterations suggest activation and structural remodeling. Conversely, C9-FTD donors have fewer high-quality neuronal nuclei in the frontal cortex and numerous gene expression changes in glial cells. These findings highlight a context-dependent molecular disruption in C9-ALS and C9-FTD, indicating unique effects across cell types, brain regions, and diseases.
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Affiliation(s)
- Junhao Li
- Department of Cognitive Science, University of California San Diego, La Jolla, CA, 92037, US
| | - Manoj K Jaiswal
- Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, US
| | - Jo-Fan Chien
- Department of Physics, University of California San Diego, La Jolla, CA, 92037, US
| | - Alexey Kozlenkov
- Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, US
| | - Jinyoung Jung
- Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, US
| | - Ping Zhou
- Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, US
| | | | - Luc J Pregent
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, US
| | | | - Dennis W Dickson
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, US
| | | | - Eran A Mukamel
- Department of Cognitive Science, University of California San Diego, La Jolla, CA, 92037, US.
| | - Stella Dracheva
- Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, US.
- Research & Development and VISN2 MIREC, James J, Peters VA Medical Center, Bronx, NY, 10468, US.
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16
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Paryani F, Kwon JS, Ng CW, Madden N, Ofori K, Tang A, Lu H, Li J, Mahajan A, Davidson SM, Basile A, McHugh C, Vonsattel JP, Hickman R, Zody M, Houseman DE, Goldman JE, Yoo AS, Menon V, Al-Dalahmah O. Multi-OMIC analysis of Huntington disease reveals a neuroprotective astrocyte state. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.08.556867. [PMID: 37745577 PMCID: PMC10515780 DOI: 10.1101/2023.09.08.556867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Huntington disease (HD) is an incurable neurodegenerative disease characterized by neuronal loss and astrogliosis. One hallmark of HD is the selective neuronal vulnerability of striatal medium spiny neurons. To date, the underlying mechanisms of this selective vulnerability have not been fully defined. Here, we employed a multi-omic approach including single nucleus RNAseq (snRNAseq), bulk RNAseq, lipidomics, HTT gene CAG repeat length measurements, and multiplexed immunofluorescence on post-mortem brain tissue from multiple brain regions of HD and control donors. We defined a signature of genes that is driven by CAG repeat length and found it enriched in astrocytic and microglial genes. Moreover, weighted gene correlation network analysis showed loss of connectivity of astrocytic and microglial modules in HD and identified modules that correlated with CAG-repeat length which further implicated inflammatory pathways and metabolism. We performed lipidomic analysis of HD and control brains and identified several lipid species that correlate with HD grade, including ceramides and very long chain fatty acids. Integration of lipidomics and bulk transcriptomics identified a consensus gene signature that correlates with HD grade and HD lipidomic abnormalities and implicated the unfolded protein response pathway. Because astrocytes are critical for brain lipid metabolism and play important roles in regulating inflammation, we analyzed our snRNAseq dataset with an emphasis on astrocyte pathology. We found two main astrocyte types that spanned multiple brain regions; these types correspond to protoplasmic astrocytes, and fibrous-like - CD44-positive, astrocytes. HD pathology was differentially associated with these cell types in a region-specific manner. One protoplasmic astrocyte cluster showed high expression of metallothionein genes, the depletion of this cluster positively correlated with the depletion of vulnerable medium spiny neurons in the caudate nucleus. We confirmed that metallothioneins were increased in cingulate HD astrocytes but were unchanged or even decreased in caudate astrocytes. We combined existing genome-wide association studies (GWAS) with a GWA study conducted on HD patients from the original Venezuelan cohort and identified a single-nucleotide polymorphism in the metallothionein gene locus associated with delayed age of onset. Functional studies found that metallothionein overexpressing astrocytes are better able to buffer glutamate and were neuroprotective of patient-derived directly reprogrammed HD MSNs as well as against rotenone-induced neuronal death in vitro. Finally, we found that metallothionein-overexpressing astrocytes increased the phagocytic activity of microglia in vitro and increased the expression of genes involved in fatty acid binding. Together, we identified an astrocytic phenotype that is regionally-enriched in less vulnerable brain regions that can be leveraged to protect neurons in HD.
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Affiliation(s)
- Fahad Paryani
- Department of Neurology, Columbia University Irving Medical Center
| | - Ji-Sun Kwon
- Washington University School of Medicine in St. Louis
| | - Chris W Ng
- Massachusetts Institute of Technology, Department of Biological Engineering
| | - Nacoya Madden
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | - Kenneth Ofori
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | - Alice Tang
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | - Hong Lu
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | - Juncheng Li
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | - Aayushi Mahajan
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | - Shawn M. Davidson
- Princeton University, Lewis-Sigler Institute for Integrative Genomics
| | | | | | - Jean Paul Vonsattel
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | - Richard Hickman
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | | | - David E. Houseman
- Massachusetts Institute of Technology, Department of Biological Engineering
| | - James E. Goldman
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
| | - Andrew S. Yoo
- Washington University School of Medicine in St. Louis
| | - Vilas Menon
- Department of Neurology, Columbia University Irving Medical Center
| | - Osama Al-Dalahmah
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
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17
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Panchenko PE, Hippauf L, Konsman JP, Badaut J. Do astrocytes act as immune cells after pediatric TBI? Neurobiol Dis 2023; 185:106231. [PMID: 37468048 PMCID: PMC10530000 DOI: 10.1016/j.nbd.2023.106231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/28/2023] [Accepted: 07/15/2023] [Indexed: 07/21/2023] Open
Abstract
Astrocytes are in contact with the vasculature, neurons, oligodendrocytes and microglia, forming a local network with various functions critical for brain homeostasis. One of the primary responders to brain injury are astrocytes as they detect neuronal and vascular damage, change their phenotype with morphological, proteomic and transcriptomic transformations for an adaptive response. The role of astrocytic responses in brain dysfunction is not fully elucidated in adult, and even less described in the developing brain. Children are vulnerable to traumatic brain injury (TBI), which represents a leading cause of death and disability in the pediatric population. Pediatric brain trauma, even with mild severity, can lead to long-term health complications, such as cognitive impairments, emotional disorders and social dysfunction later in life. To date, the underlying pathophysiology is still not fully understood. In this review, we focus on the astrocytic response in pediatric TBI and propose a potential immune role of the astrocyte in response to trauma. We discuss the contribution of astrocytes in the local inflammatory cascades and secretion of various immunomodulatory factors involved in the recruitment of local microglial cells and peripheral immune cells through cerebral blood vessels. Taken together, we propose that early changes in the astrocytic phenotype can alter normal development of the brain, with long-term consequences on neurological outcomes, as described in preclinical models and patients.
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Affiliation(s)
| | - Lea Hippauf
- CNRS UMR 5536 RMSB-University of Bordeaux, Bordeaux, France
| | | | - Jerome Badaut
- CNRS UMR 5536 RMSB-University of Bordeaux, Bordeaux, France; Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
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18
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Mihailova V, Stoyanova II, Tonchev AB. Glial Populations in the Human Brain Following Ischemic Injury. Biomedicines 2023; 11:2332. [PMID: 37760773 PMCID: PMC10525766 DOI: 10.3390/biomedicines11092332] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 09/29/2023] Open
Abstract
There is a growing interest in glial cells in the central nervous system due to their important role in maintaining brain homeostasis under physiological conditions and after injury. A significant amount of evidence has been accumulated regarding their capacity to exert either pro-inflammatory or anti-inflammatory effects under different pathological conditions. In combination with their proliferative potential, they contribute not only to the limitation of brain damage and tissue remodeling but also to neuronal repair and synaptic recovery. Moreover, reactive glial cells can modulate the processes of neurogenesis, neuronal differentiation, and migration of neurons in the existing neural circuits in the adult brain. By discovering precise signals within specific niches, the regulation of sequential processes in adult neurogenesis holds the potential to unlock strategies that can stimulate the generation of functional neurons, whether in response to injury or as a means of addressing degenerative neurological conditions. Cerebral ischemic stroke, a condition falling within the realm of acute vascular disorders affecting the circulation in the brain, stands as a prominent global cause of disability and mortality. Extensive investigations into glial plasticity and their intricate interactions with other cells in the central nervous system have predominantly relied on studies conducted on experimental animals, including rodents and primates. However, valuable insights have also been gleaned from in vivo studies involving poststroke patients, utilizing highly specialized imaging techniques. Following the attempts to map brain cells, the role of various transcription factors in modulating gene expression in response to cerebral ischemia is gaining increasing popularity. Although the results obtained thus far remain incomplete and occasionally ambiguous, they serve as a solid foundation for the development of strategies aimed at influencing the recovery process after ischemic brain injury.
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Affiliation(s)
- Victoria Mihailova
- Department of Anatomy and Cell Biology, Faculty of Medicine, Medical University Varna, 9000 Varna, Bulgaria; (I.I.S.); (A.B.T.)
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19
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Dai DL, Li M, Lee EB. Human Alzheimer's disease reactive astrocytes exhibit a loss of homeostastic gene expression. Acta Neuropathol Commun 2023; 11:127. [PMID: 37533101 PMCID: PMC10398957 DOI: 10.1186/s40478-023-01624-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 07/14/2023] [Indexed: 08/04/2023] Open
Abstract
Astrocytes are one of the brain's major cell types and are responsible for maintaining neuronal homeostasis via regulating the extracellular environment, providing metabolic support, and modulating synaptic activity. In neurodegenerative diseases, such as Alzheimer's disease, astrocytes can take on a hypertrophic appearance. These reactive astrocytes are canonically associated with increases in cytoskeletal proteins, such as glial fibrillary acidic protein and vimentin. However, the molecular alterations that characterize astrocytes in human disease tissues have not been extensively studied with single cell resolution. Using single nucleus RNA sequencing data from normal, pathologic aging, and Alzheimer's disease brains, we identified the transcriptomic changes associated with reactive astrocytes. Deep learning-based clustering algorithms denoised expression data for 17,012 genes and clustered 15,529 astrocyte nuclei, identifying protoplasmic, gray matter and fibrous, white matter astrocyte clusters. RNA trajectory analyses revealed a spectrum of reactivity within protoplasmic astrocytes characterized by a modest increase of reactive genes and a marked decrease in homeostatic genes. Amyloid but not tau pathology correlated with astrocyte reactivity. To identify reactivity-associated genes, linear regressions of gene expression versus reactivity were used to identify the top 52 upregulated and 144 downregulated genes. Gene Ontology analysis revealed that upregulated genes were associated with cellular growth, responses to metal ions, inflammation, and proteostasis. Downregulated genes were involved in cellular interactions, neuronal development, ERBB signaling, and synapse regulation. Transcription factors were significantly enriched among the downregulated genes. Using co-immunofluorescence staining of Alzheimer's disease brain tissues, we confirmed pathologic downregulation of ERBB4 and transcription factor NFIA in reactive astrocytes. Our findings reveal that protoplasmic, gray matter astrocytes in Alzheimer's disease exist within a spectrum of reactivity that is marked by a strong loss of normal function.
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Affiliation(s)
- David L Dai
- Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA
| | - Mingyao Li
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA
| | - Edward B Lee
- Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
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20
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Madden N, Mei YZJ, Jakubiak K, Li J, Hargus G, Goldman JE, Al-Dalahmah O. The link between SARS-CoV-2 related microglial reactivity and astrocyte pathology in the inferior olivary nucleus. Front Neurosci 2023; 17:1198219. [PMID: 37483351 PMCID: PMC10359900 DOI: 10.3389/fnins.2023.1198219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/05/2023] [Indexed: 07/25/2023] Open
Abstract
The pathological involvement of the central nervous system in SARS-CoV2 (COVID-19) patients is established. The burden of pathology is most pronounced in the brain stem including the medulla oblongata. Hypoxic/ischemic damage is the most frequent neuropathologic abnormality. Other neuropathologic features include neuronophagia, microglial nodules, and hallmarks of neurodegenerative diseases: astrogliosis and microglial reactivity. It is still unknown if these pathologies are secondary to hypoxia versus a combination of inflammatory response combined with hypoxia. It is also unknown how astrocytes react to neuroinflammation in COVID-19, especially considering evidence supporting the neurotoxicity of certain astrocytic phenotypes. This study aims to define the link between astrocytic and microglial pathology in COVID-19 victims in the inferior olivary nucleus, which is one of the most severely affected brain regions in COVID-19, and establish whether COVID-19 pathology is driven by hypoxic damage. Here, we conducted neuropathologic assessments and multiplex-immunofluorescence studies on the medulla oblongata of 18 COVID-19, 10 pre-pandemic patients who died of acute respiratory distress syndrome (ARDS), and 7-8 control patients with no ARDS or COVID-19. The comparison of ARDS and COVID-19 allows us to identify whether the pathology in COVID-19 can be explained by hypoxia alone, which is common to both conditions. Our results showed increased olivary astrogliosis in ARDS and COVID-19. However, microglial density and microglial reactivity were increased only in COVID-19, in a region-specific manner. Also, olivary hilar astrocytes increased YKL-40 (CHI3L1) in COVID-19, but to a lesser extent than ARDS astrocytes. COVID-19 astrocytes also showed lower levels of Aquaporin-4 (AQP4), and Metallothionein-3 in subsets of COVID-19 brain regions. Cluster analysis on immunohistochemical attributes of astrocytes and microglia identified ARDS and COVID-19 clusters with correlations to clinical history and disease course. Our results indicate that olivary glial pathology and neuroinflammation in the COVID-19 cannot be explained solely by hypoxia and suggest that failure of astrocytes to upregulate the anti-inflammatory YKL-40 may contribute to the neuroinflammation. Notwithstanding the limitations of retrospective studies in establishing causality, our experimental design cannot adequately control for factors external to our design. Perturbative studies are needed to confirm the role of the above-described astrocytic phenotypes in neuroinflammation.
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Affiliation(s)
| | | | | | | | | | | | - Osama Al-Dalahmah
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, United States
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21
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Kruk PK, Nader K, Skupien-Jaroszek A, Wójtowicz T, Buszka A, Olech-Kochańczyk G, Wilczynski GM, Worch R, Kalita K, Włodarczyk J, Dzwonek J. Astrocytic CD44 Deficiency Reduces the Severity of Kainate-Induced Epilepsy. Cells 2023; 12:1483. [PMID: 37296604 PMCID: PMC10252631 DOI: 10.3390/cells12111483] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/05/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Epilepsy affects millions of people worldwide, yet we still lack a successful treatment for all epileptic patients. Most of the available drugs modulate neuronal activity. Astrocytes, the most abundant cells in the brain, may constitute alternative drug targets. A robust expansion of astrocytic cell bodies and processes occurs after seizures. Highly expressed in astrocytes, CD44 adhesion protein is upregulated during injury and is suggested to be one of the most important proteins associated with epilepsy. It connects the astrocytic cytoskeleton to hyaluronan in the extracellular matrix, influencing both structural and functional aspects of brain plasticity. METHODS Herein, we used transgenic mice with an astrocyte CD44 knockout to evaluate the impact of the hippocampal CD44 absence on the development of epileptogenesis and ultrastructural changes at the tripartite synapse. RESULTS We demonstrated that local, virally-induced CD44 deficiency in hippocampal astrocytes reduces reactive astrogliosis and decreases the progression of kainic acid-induced epileptogenesis. We also observed that CD44 deficiency resulted in structural changes evident in a higher dendritic spine number along with a lower percentage of astrocyte-synapse contacts, and decreased post-synaptic density size in the hippocampal molecular layer of the dentate gyrus. CONCLUSIONS Overall, our study indicates that CD44 signaling may be important for astrocytic coverage of synapses in the hippocampus and that alterations of astrocytes translate to functional changes in the pathology of epilepsy.
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Affiliation(s)
- Patrycja K. Kruk
- Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Karolina Nader
- Laboratory of Neurobiology, Nencki-EMBL Partnership for Neural Plasticity and Brain Disorders-Braincity, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Anna Skupien-Jaroszek
- Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Tomasz Wójtowicz
- Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Anna Buszka
- Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Gabriela Olech-Kochańczyk
- Laboratory of Molecular and Structural Neuromorphology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Grzegorz M. Wilczynski
- Laboratory of Molecular and Structural Neuromorphology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Remigiusz Worch
- Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Katarzyna Kalita
- Laboratory of Neurobiology, Nencki-EMBL Partnership for Neural Plasticity and Brain Disorders-Braincity, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Jakub Włodarczyk
- Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
| | - Joanna Dzwonek
- Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteura St, 02-093 Warsaw, Poland
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22
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Brown TG, Thayer MN, VanTreeck JG, Zarate N, Hart DW, Heilbronner S, Gomez-Pastor R. Striatal spatial heterogeneity, clustering, and white matter association of GFAP + astrocytes in a mouse model of Huntington's disease. Front Cell Neurosci 2023; 17:1094503. [PMID: 37187609 PMCID: PMC10175581 DOI: 10.3389/fncel.2023.1094503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 04/10/2023] [Indexed: 05/17/2023] Open
Abstract
Introduction Huntington's disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Neuronal dysfunction and loss in HD is accompanied by increased astrocyte density and astrocyte pathology. Astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Studying whether mutant Huntingtin (HTT) alters specific subtypes of astrocytes is necessary to understand their relative contribution to HD. Methods Here, we studied whether astrocytes expressing two different markers; glial fibrillary acidic protein (GFAP), associated with astrocyte activation, and S100 calcium-binding protein B (S100B), a marker of matured astrocytes and inflammation, were differentially altered in HD. Results First, we found three distinct populations in the striatum of WT and symptomatic zQ175 mice: GFAP+, S100B+, and dual GFAP+S100B+. The number of GFAP+ and S100B+ astrocytes throughout the striatum was increased in HD mice compared to WT, coinciding with an increase in HTT aggregation. Overlap between GFAP and S100B staining was expected, but dual GFAP+S100B+ astrocytes only accounted for less than 10% of all tested astrocytes and the number of GFAP+S100B+ astrocytes did not differ between WT and HD, suggesting that GFAP+ astrocytes and S100B+ astrocytes are distinct types of astrocytes. Interestingly, a spatial characterization of these astrocyte subtypes in HD mice showed that while S100B+ were homogeneously distributed throughout the striatum, GFAP+ preferentially accumulated in "patches" in the dorsomedial (dm) striatum, a region associated with goal-directed behaviors. In addition, GFAP+ astrocytes in the dm striatum of zQ175 mice showed increased clustering and association with white matter fascicles and were preferentially located in areas with low HTT aggregate load. Discussion In summary, we showed that GFAP+ and S100B+ astrocyte subtypes are distinctly affected in HD and exist in distinct spatial arrangements that may offer new insights to the function of these specific astrocytes subtypes and their potential implications in HD pathology.
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Affiliation(s)
| | | | | | | | | | | | - Rocio Gomez-Pastor
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, United States
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23
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Batenburg KL, Sestito C, Cornelissen-Steijger P, van Weering JRT, Price LS, Heine VM, Scheper W. A 3D human co-culture to model neuron-astrocyte interactions in tauopathies. Biol Proced Online 2023; 25:4. [PMID: 36814189 PMCID: PMC9948470 DOI: 10.1186/s12575-023-00194-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Intraneuronal tau aggregation is the major pathological hallmark of neurodegenerative tauopathies. It is now generally acknowledged that tau aggregation also affects astrocytes in a cell non-autonomous manner. However, mechanisms involved are unclear, partly because of the lack of models that reflect the situation in the human tauopathy brain. To accurately model neuron-astrocyte interaction in tauopathies, there is a need for a model that contains both human neurons and human astrocytes, intraneuronal tau pathology and mimics the three-dimensional architecture of the brain. RESULTS Here we established a novel 100-200 µm thick 3D human neuron/astrocyte co-culture model of tau pathology, comprising homogenous populations of hiPSC-derived neurons and primary human astrocytes in microwell format. Using confocal, electron and live microscopy, we validate the procedures by showing that neurons in the 3D co-culture form pre- and postsynapses and display spontaneous calcium transients within 4 weeks. Astrocytes in the 3D co-culture display bipolar and stellate morphologies with extensive processes that ensheath neuronal somas, spatially align with axons and dendrites and can be found perisynaptically. The complex morphology of astrocytes and the interaction with neurons in the 3D co-culture mirrors that in the human brain, indicating the model's potential to study physiological and pathological neuron-astrocyte interaction in vitro. Finally, we successfully implemented a methodology to introduce seed-independent intraneuronal tau aggregation in the 3D co-culture, enabling study of neuron-astrocyte interaction in early tau pathogenesis. CONCLUSIONS Altogether, these data provide proof-of-concept for the utility of this rapid, miniaturized, and standardized 3D model for cell type-specific manipulations, such as the intraneuronal pathology that is associated with neurodegenerative disorders.
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Affiliation(s)
- Kevin L. Batenburg
- grid.12380.380000 0004 1754 9227Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience - Neurodegeneration, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
| | - Claudia Sestito
- Crown Bioscience Netherlands B.V. (Formerly OcellO B.V.), Leiden, The Netherlands ,grid.484519.5Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Child and Adolescent Psychiatry, Amsterdam Neuroscience, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
| | - Paulien Cornelissen-Steijger
- grid.484519.5Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Child and Adolescent Psychiatry, Amsterdam Neuroscience, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands ,grid.484519.5Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
| | - Jan R. T. van Weering
- grid.12380.380000 0004 1754 9227Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience - Neurodegeneration, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands ,grid.484519.5Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Human Genetics, Amsterdam Neuroscience - Neurodegeneration, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
| | - Leo S. Price
- Crown Bioscience Netherlands B.V. (Formerly OcellO B.V.), Leiden, The Netherlands
| | - Vivi M. Heine
- grid.484519.5Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Child and Adolescent Psychiatry, Amsterdam Neuroscience, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands ,grid.484519.5Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
| | - Wiep Scheper
- Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience - Neurodegeneration, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands. .,Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Human Genetics, Amsterdam Neuroscience - Neurodegeneration, De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
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24
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Nor Nazli NA, Muthuraju S, Ahmad F, Mohamed Yusoff AA, Jaafar H, Shamsuddin S, Abdullah JM. Characterisation of Primary Human Hippocampal Astrocyte Cell Culture Following Exposure to Hypoxia. Malays J Med Sci 2023; 30:92-106. [PMID: 36875187 PMCID: PMC9984107 DOI: 10.21315/mjms2023.30.1.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/01/2022] [Indexed: 03/05/2023] Open
Abstract
Background The present study aimed to understand the characterisation of human hippocampal astrocyte following hypoxia exposure. Based on the preliminary screening, 15 min was chosen as the time point and the cells were exposed to different oxygen percentages. Methods The Trypan blue viability assay used to examine cell death. Immunofluorescence assay, glial fibrillary acidic protein (GFAP) was used to portray the morphology of astrocytes. The hypoxia-inducible factor 1 (HIF-1) staining was performed to confirm hypoxia induced cell death and there was a dramatic expression of HIF-1α displayed in exposed astrocyte cells compared to the control. In molecular level, genes were chosen, such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH), GFAP, HIF-1α and B-cell lymphoma 2 (Bcl-2) and ran the reverse transcription-polymerase chain reaction (RT-PCR). Results Microscope revealed a filamentous and clear nucleus appearance in a control whereas the rupture nuclei with no rigid structure of the cell were found in the 3% oxygen. The control and hypoxia cells were also stained with the annexin V-fluorescein isothiocyanate (annexin V-FITC). Fluorescence microscope reveals astrocyte cells after hypoxia showed higher expression of nuclei but not in control. Merging PI and FITC showed the differences of nuclei expression between the control and hypoxia. In the molecular analysis, there were significant changes of GFAP, HIF-1α and Bcl-2 in hypoxia exposed cells when compared to the control group. Conclusion Cells that were exposed to hypoxia (3% oxygen for 15 min) clearly showed damage. General view of human hippocampal astrocyte genomic response to hypoxia was obtained.
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Affiliation(s)
- Nurul Atikah Nor Nazli
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Sangu Muthuraju
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Farizan Ahmad
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Hasnan Jaafar
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Shaharum Shamsuddin
- Department of Biomedicine, School of Health Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Jafri Malin Abdullah
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
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25
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Degl’Innocenti E, Dell’Anno MT. Human and mouse cortical astrocytes: a comparative view from development to morphological and functional characterization. Front Neuroanat 2023; 17:1130729. [PMID: 37139179 PMCID: PMC10150887 DOI: 10.3389/fnana.2023.1130729] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 03/28/2023] [Indexed: 05/05/2023] Open
Abstract
The vision of astroglia as a bare scaffold to neuronal circuitry has been largely overturned. Astrocytes exert a neurotrophic function, but also take active part in supporting synaptic transmission and in calibrating blood circulation. Many aspects of their functioning have been unveiled from studies conducted in murine models, however evidence is showing many differences between mouse and human astrocytes starting from their development and encompassing morphological, transcriptomic and physiological variations when they achieve complete maturation. The evolutionary race toward superior cognitive abilities unique to humans has drastically impacted neocortex structure and, together with neuronal circuitry, astrocytes have also been affected with the acquisition of species-specific properties. In this review, we summarize diversities between murine and human astroglia, with a specific focus on neocortex, in a panoramic view that starts with their developmental origin to include all structural and molecular differences that mark the uniqueness of human astrocytes.
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Affiliation(s)
- Elisa Degl’Innocenti
- Fondazione Pisana per la Scienza ONLUS, San Giuliano Terme, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Maria Teresa Dell’Anno
- Fondazione Pisana per la Scienza ONLUS, San Giuliano Terme, Italy
- *Correspondence: Maria Teresa Dell’Anno,
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26
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Falcone C, Martínez-Cerdeño V. Astrocyte evolution and human specificity. Neural Regen Res 2023; 18:131-132. [PMID: 35799529 PMCID: PMC9241407 DOI: 10.4103/1673-5374.340405] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/18/2021] [Accepted: 01/12/2022] [Indexed: 12/02/2022] Open
Affiliation(s)
- Carmen Falcone
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine; Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children of Northern California, Sacramento, CA, USA
| | - Verónica Martínez-Cerdeño
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine; Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children of Northern California, Sacramento, CA, USA
- MIND Institute, UC Davis Medical Center, Sacramento, CA, USA
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27
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Pai B, Tome-Garcia J, Cheng WS, Nudelman G, Beaumont KG, Ghatan S, Panov F, Caballero E, Sarpong K, Marcuse L, Yoo J, Jiang Y, Schaefer A, Akbarian S, Sebra R, Pinto D, Zaslavsky E, Tsankova NM. High-resolution transcriptomics informs glial pathology in human temporal lobe epilepsy. Acta Neuropathol Commun 2022; 10:149. [PMID: 36274170 PMCID: PMC9590125 DOI: 10.1186/s40478-022-01453-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 09/30/2022] [Indexed: 11/16/2022] Open
Abstract
The pathophysiology of epilepsy underlies a complex network dysfunction between neurons and glia, the molecular cell type-specific contributions of which remain poorly defined in the human disease. In this study, we validated a method that simultaneously isolates neuronal (NEUN +), astrocyte (PAX6 + NEUN-), and oligodendroglial progenitor (OPC) (OLIG2 + NEUN-) enriched nuclei populations from non-diseased, fresh-frozen human neocortex and then applied it to characterize the distinct transcriptomes of such populations isolated from electrode-mapped temporal lobe epilepsy (TLE) surgical samples. Nuclear RNA-seq confirmed cell type specificity and informed both common and distinct pathways associated with TLE in astrocytes, OPCs, and neurons. Compared to postmortem control, the transcriptome of epilepsy astrocytes showed downregulation of mature astrocyte functions and upregulation of development-related genes. To gain further insight into glial heterogeneity in TLE, we performed single cell transcriptomics (scRNA-seq) on four additional human TLE samples. Analysis of the integrated TLE dataset uncovered a prominent subpopulation of glia that express a hybrid signature of both reactive astrocyte and OPC markers, including many cells with a mixed GFAP + OLIG2 + phenotype. A further integrated analysis of this TLE scRNA-seq dataset and a previously published normal human temporal lobe scRNA-seq dataset confirmed the unique presence of hybrid glia only in TLE. Pseudotime analysis revealed cell transition trajectories stemming from this hybrid population towards both OPCs and reactive astrocytes. Immunofluorescence studies in human TLE samples confirmed the rare presence of GFAP + OLIG2 + glia, including some cells with proliferative activity, and functional analysis of cells isolated directly from these samples disclosed abnormal neurosphere formation in vitro. Overall, cell type-specific isolation of glia from surgical epilepsy samples combined with transcriptomic analyses uncovered abnormal glial subpopulations with de-differentiated phenotype, motivating further studies into the dysfunctional role of reactive glia in temporal lobe epilepsy.
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Affiliation(s)
- Balagopal Pai
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jessica Tome-Garcia
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Wan Sze Cheng
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - German Nudelman
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kristin G Beaumont
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Icahn Institute for Data Science and Genomic Technology, New York, NY, 10029, USA
| | - Saadi Ghatan
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Fedor Panov
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Elodia Caballero
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kwadwo Sarpong
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Icahn Institute for Data Science and Genomic Technology, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Lara Marcuse
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jiyeoun Yoo
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yan Jiang
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Anne Schaefer
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Schahram Akbarian
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Robert Sebra
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Icahn Institute for Data Science and Genomic Technology, New York, NY, 10029, USA
| | - Dalila Pinto
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Icahn Institute for Data Science and Genomic Technology, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Elena Zaslavsky
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Nadejda M Tsankova
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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28
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Toledano-Díaz A, Álvarez MI, Toledano A. The relationships between neuroglial alterations and neuronal changes in Alzheimer's disease, and the related controversies I: Gliopathogenesis and glioprotection. J Cent Nerv Syst Dis 2022; 14:11795735221128703. [PMID: 36238130 PMCID: PMC9551335 DOI: 10.1177/11795735221128703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Since Alois Alzheimer described the pathology of Alzheimer's disease in 1907, an increasing number of studies have attempted to discover its causes and possible ways to treat it. For decades, research has focused on neuronal degeneration and the disruption to the neural circuits that occurs during disease progression, undervaluing in some extent the alterations to glial cells even though these alterations were described in the very first studies of this disease. In recent years, it has been recognized that different families of neuroglia are not merely support cells for neurons but rather key and active elements in the physiology and pathology of the nervous system. Alterations to different types of neuroglia (especially astroglia and microglia but also mature oligodendroglia and oligodendroglial progenitors) have been identified in the initial neuropathological changes that lead to dementia, suggesting that they may represent therapeutic targets to prevent neurodegeneration. In this review, based on our own studies and on the relevant scientific literature, we argue that a careful and in-depth study of glial cells will be fundamental to understanding the origin and progression of Alzheimer's disease. In addition, we analyze the main issues regarding the neuroprotective and neurotoxic role of neuroglial changes, reactions and/or involutions in both humans with Alzheimer's disease and in experimental models of this condition.
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29
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Kruyer A. Astrocyte Heterogeneity in Regulation of Synaptic Activity. Cells 2022; 11:cells11193135. [PMID: 36231097 PMCID: PMC9562199 DOI: 10.3390/cells11193135] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/02/2022] [Accepted: 10/02/2022] [Indexed: 02/07/2023] Open
Abstract
Our awareness of the number of synapse regulatory functions performed by astroglia is rapidly expanding, raising interesting questions regarding astrocyte heterogeneity and specialization across brain regions. Whether all astrocytes are poised to signal in a multitude of ways, or are instead tuned to surrounding synapses and how astroglial signaling is altered in psychiatric and cognitive disorders are fundamental questions for the field. In recent years, molecular and morphological characterization of astroglial types has broadened our ability to design studies to better analyze and manipulate specific functions of astroglia. Recent data emerging from these studies will be discussed in depth in this review. I also highlight remaining questions emerging from new techniques recently applied toward understanding the roles of astrocytes in synapse regulation in the adult brain.
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Affiliation(s)
- Anna Kruyer
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
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30
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Yim A, Smith C, Brown AM. Osteopontin/secreted phosphoprotein-1 harnesses glial-, immune-, and neuronal cell ligand-receptor interactions to sense and regulate acute and chronic neuroinflammation. Immunol Rev 2022; 311:224-233. [PMID: 35451082 PMCID: PMC9790650 DOI: 10.1111/imr.13081] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 12/31/2022]
Abstract
Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein-1 (SPP1) is a fascinating, multifunctional protein expressed in a number of cell types that functions not only in intercellular communication, but also in the extracellular matrix (ECM). OPN/SPP1 possesses cytokine, chemokine, and signal transduction functions by virtue of modular structural motifs that provide interaction surfaces for integrins and CD44-variant receptors. In humans, there are three experimentally verified splice variants of OPN/SPP1 and CD44's ten exons are also alternatively spiced in a cell/tissue-specific manner, although very little is known about how this is regulated in the central nervous system (CNS). Post-translational modifications of phosphorylation, glycosylation, and localized cleavage by specific proteases in the cells and tissues where OPN/SPP1 functions, provides additional layers of specificity. However, the former make elucidating the exact molecular mechanisms of OPN/SPP1 function more complex. Flexibility in OPN/SPP1 structure and its engagement with integrins having the ability to transmit signals in inside-out and outside-in direction, is likely why OPN/SPP1 can serve as an early detector of inflammation and ongoing tissue damage in response to cancer, stroke, traumatic brain injury, pathogenic infection, and neurodegeneration, processes that impair tissue homeostasis. This review will focus on what is currently known about OPN/SPP1 function in the brain.
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Affiliation(s)
- Ashley Yim
- NeurologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Christian Smith
- NeurologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Amanda M. Brown
- NeurologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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31
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Gorina YV, Salmina AB, Erofeev AI, Gerasimov EI, Bolshakova AV, Balaban PM, Bezprozvanny IB, Vlasova OL. Astrocyte Activation Markers. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:851-870. [PMID: 36180985 DOI: 10.1134/s0006297922090012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 06/16/2023]
Abstract
Astrocytes are the most common type of glial cells that provide homeostasis and protection of the central nervous system. Important specific characteristic of astrocytes is manifestation of morphological heterogeneity, which is directly dependent on localization in a particular area of the brain. Astrocytes can integrate into neural networks and keep neurons active in various areas of the brain. Moreover, astrocytes express a variety of receptors, channels, and membrane transporters, which underlie their peculiar metabolic activity, and, hence, determine plasticity of the central nervous system during development and aging. Such complex structural and functional organization of astrocytes requires the use of modern methods for their identification and analysis. Considering the important fact that determining the most appropriate marker for polymorphic and multiple subgroups of astrocytes is of decisive importance for studying their multifunctionality, this review presents markers, modern imaging techniques, and identification of astrocytes, which comprise a valuable resource for studying structural and functional properties of astrocytes, as well as facilitate better understanding of the extent to which astrocytes contribute to neuronal activity.
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Affiliation(s)
- Yana V Gorina
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 194091, Russia.
- Research Institute of Molecular Medicine and Pathobiochemistry, Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, 660022, Russia
| | - Alla B Salmina
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 194091, Russia
- Research Institute of Molecular Medicine and Pathobiochemistry, Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, 660022, Russia
- Laboratory of Neurobiology and Tissue Engineering, Brain Institute, Research Center of Neurology, Moscow, 105064, Russia
| | - Alexander I Erofeev
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 194091, Russia
| | - Evgeniy I Gerasimov
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 194091, Russia
| | - Anastasia V Bolshakova
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 194091, Russia
| | - Pavel M Balaban
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 194091, Russia
- Laboratory of Cellular Neurobiology of Learning, Institute of Higher Nervous Activity, Moscow, 117485, Russia
| | - Ilya B Bezprozvanny
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 194091, Russia
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Olga L Vlasova
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, 194091, Russia
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32
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Aleksandrova MA, Sukhinich KK. Astrocytes of the Brain: Retinue Plays the King. Russ J Dev Biol 2022. [DOI: 10.1134/s1062360422040026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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33
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Goldman JE. Alzheimer Type I Astrocytes: Still Mysterious Cells. J Neuropathol Exp Neurol 2022; 81:588-595. [PMID: 35689655 DOI: 10.1093/jnen/nlac043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Over 100 years ago, von Hösslein and Alzheimer described enlarged and multinucleated astrocytes in the brains of patients with Wilson disease. These odd astrocytes, now well known to neuropathologists, are present in a large variety of neurological disorders, and yet the mechanisms underlying their generation and their functional attributes are still not well understood. They undergo abnormal mitoses and fail to accomplish cytokinesis, resulting in multinucleation. Oxidative stress, hypoxia, and inflammation may be contributing pathologies to generate these astrocytes. The abnormal mitoses occur from changes in cell shape, the accumulation of cytoplasmic proteins, and the mislocalization of many of the important molecules whose coordination is necessary for proper mitotic spindle formation. Modern technologies will be able to characterize their abnormalities and solve century old questions of their form and function.
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Affiliation(s)
- James E Goldman
- From the Division of Neuropathology, Department of Pathology & Cell Biology, Columbia University Vagelos College of Physicians and Surgeons and The Taub Institute for Research on Alzheimer's Disease and Aging, NY-Presbyterian Columbia University Irving Medical Center, New York, New York, USA
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34
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Voronkov DN, Stavrovskaya AV, Guschina AS, Olshansky AS, Lebedeva OS, Eremeev AV, Lagarkova MA. Morphological Characterization of Astrocytes in a Xenograft of Human iPSCDerived Neural Precursor Cells. Acta Naturae 2022; 14:100-108. [PMID: 36348713 PMCID: PMC9611864 DOI: 10.32607/actanaturae.11710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/22/2022] [Indexed: 09/07/2024] Open
Abstract
Transplantation of a mixed astrocyte and neuron culture is of interest in the development of cell therapies for neurodegenerative diseases. In this case, an assessment of engraftment requires a detailed morphological characterization, in particular an analysis of the neuronal and glial populations. In the experiment performed, human iPSC-derived neural progenitors transplanted into a rat striatum produced a mixed neuron and astrocyte population in vivo by the sixth month after transplantation. The morphological characteristics and neurochemical profile of the xenografted astrocytes were similar to those of mature human astroglia. Unlike neurons, astrocytes migrated to the surrounding structures and the density and pattern of their distribution in the striatum and cerebral cortex differed, which indicates that the microenvironment affects human glia integration. The graft was characterized by the zonal features of glial cell morphology, which was a reflection of cell maturation in the central area, glial shaft formation around the transplanted neurons, and migration to the surrounding structures.
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Affiliation(s)
| | | | | | | | - O. S. Lebedeva
- Federal Research and Clinical Center of Physical Chemical Medicine of the Federal Medical and Biological Agency of the Russian Federation, Moscow, 119435 Russia
| | - A. V. Eremeev
- Federal Research and Clinical Center of Physical Chemical Medicine of the Federal Medical and Biological Agency of the Russian Federation, Moscow, 119435 Russia
| | - M. A. Lagarkova
- Federal Research and Clinical Center of Physical Chemical Medicine of the Federal Medical and Biological Agency of the Russian Federation, Moscow, 119435 Russia
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35
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Fang R, Xia C, Close JL, Zhang M, He J, Huang Z, Halpern AR, Long B, Miller JA, Lein ES, Zhuang X. Conservation and divergence of cortical cell organization in human and mouse revealed by MERFISH. Science 2022; 377:56-62. [PMID: 35771910 PMCID: PMC9262715 DOI: 10.1126/science.abm1741] [Citation(s) in RCA: 156] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The human cerebral cortex has tremendous cellular diversity. How different cell types are organized in the human cortex and how cellular organization varies across species remain unclear. In this study, we performed spatially resolved single-cell profiling of 4000 genes using multiplexed error-robust fluorescence in situ hybridization (MERFISH), identified more than 100 transcriptionally distinct cell populations, and generated a molecularly defined and spatially resolved cell atlas of the human middle and superior temporal gyrus. We further explored cell-cell interactions arising from soma contact or proximity in a cell type-specific manner. Comparison of the human and mouse cortices showed conservation in the laminar organization of cells and differences in somatic interactions across species. Our data revealed human-specific cell-cell proximity patterns and a markedly increased enrichment for interactions between neurons and non-neuronal cells in the human cortex.
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Affiliation(s)
- Rongxin Fang
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA
| | - Chenglong Xia
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA
| | | | - Meng Zhang
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA
| | - Jiang He
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA
| | - Zhengkai Huang
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA
| | - Aaron R. Halpern
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA
| | - Brian Long
- Allen Institute for Brain Science, Seattle, WA 98109, USA
| | | | - Ed S. Lein
- Allen Institute for Brain Science, Seattle, WA 98109, USA
| | - Xiaowei Zhuang
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA
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36
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Region-Specific Characteristics of Astrocytes and Microglia: A Possible Involvement in Aging and Diseases. Cells 2022; 11:cells11121902. [PMID: 35741031 PMCID: PMC9220858 DOI: 10.3390/cells11121902] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 11/17/2022] Open
Abstract
Although different regions of the brain are dedicated to specific functions, the intra- and inter-regional heterogeneity of astrocytes and microglia in these regions has not yet been fully understood. Recently, an advancement in various technologies, such as single-cell RNA sequencing, has allowed for the discovery of astrocytes and microglia with distinct molecular fingerprints and varying functions in the brain. In addition, the regional heterogeneity of astrocytes and microglia exhibits different functions in several situations, such as aging and neurodegenerative diseases. Therefore, investigating the region-specific astrocytes and microglia is important in understanding the overall function of the brain. In this review, we summarize up-to-date research on various intra- and inter-regional heterogeneities of astrocytes and microglia, and provide information on how they can be applied to aging and neurodegenerative diseases.
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37
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Degl’Innocenti E, Poloni TE, Medici V, Recupero L, Dell’Amico C, Vannini E, Borello U, Mazzanti CM, Onorati M, Dell’Anno MT. Centrin 2: A Novel Marker of Mature and Neoplastic Human Astrocytes. Front Cell Neurosci 2022; 16:858347. [PMID: 35573835 PMCID: PMC9100563 DOI: 10.3389/fncel.2022.858347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/17/2022] [Indexed: 11/13/2022] Open
Abstract
As microtubule-organizing centers (MTOCs), centrosomes play a pivotal role in cell division, neurodevelopment and neuronal maturation. Among centrosomal proteins, centrin-2 (CETN2) also contributes to DNA repair mechanisms which are fundamental to prevent genomic instability during neural stem cell pool expansion. Nevertheless, the expression profile of CETN2 in human neural stem cells and their progeny is currently unknown. To address this question, we interrogated a platform of human neuroepithelial stem (NES) cells derived from post mortem developing brain or established from pluripotent cells and demonstrated that while CETN2 retains its centrosomal location in proliferating NES cells, its expression pattern changes upon differentiation. In particular, we found that CETN2 is selectively expressed in mature astrocytes with a broad cytoplasmic distribution. We then extended our findings on human autoptic nervous tissue samples. We investigated CETN2 distribution in diverse anatomical areas along the rostro-caudal neuraxis and pointed out a peculiar topography of CETN2-labeled astrocytes in humans which was not appreciable in murine tissues, where CETN2 was mostly confined to ependymal cells. As a prototypical condition with glial overproliferation, we also explored CETN2 expression in glioblastoma multiforme (GBM), reporting a focal concentration of CETN2 in neoplastic astrocytes. This study expands CETN2 localization beyond centrosomes and reveals a unique expression pattern that makes it eligible as a novel astrocytic molecular marker, thus opening new roads to glial biology and human neural conditions.
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Affiliation(s)
- Elisa Degl’Innocenti
- Fondazione Pisana per la Scienza ONLUS, San Giuliano Terme, Italy
- Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Tino Emanuele Poloni
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation and ASP Golgi-Redaelli, Abbiategrasso, Italy
| | - Valentina Medici
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation and ASP Golgi-Redaelli, Abbiategrasso, Italy
| | - Luca Recupero
- Fondazione Pisana per la Scienza ONLUS, San Giuliano Terme, Italy
| | - Claudia Dell’Amico
- Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, Pisa, Italy
| | | | - Ugo Borello
- Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, Pisa, Italy
| | | | - Marco Onorati
- Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, Pisa, Italy
| | - Maria Teresa Dell’Anno
- Fondazione Pisana per la Scienza ONLUS, San Giuliano Terme, Italy
- *Correspondence: Maria Teresa Dell’Anno,
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38
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Garland EF, Hartnell IJ, Boche D. Microglia and Astrocyte Function and Communication: What Do We Know in Humans? Front Neurosci 2022; 16:824888. [PMID: 35250459 PMCID: PMC8888691 DOI: 10.3389/fnins.2022.824888] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/24/2022] [Indexed: 12/11/2022] Open
Abstract
Microglia and astrocytes play essential roles in the central nervous system contributing to many functions including homeostasis, immune response, blood-brain barrier maintenance and synaptic support. Evidence has emerged from experimental models of glial communication that microglia and astrocytes influence and coordinate each other and their effects on the brain environment. However, due to the difference in glial cells between humans and rodents, it is essential to confirm the relevance of these findings in human brains. Here, we aim to review the current knowledge on microglia-astrocyte crosstalk in humans, exploring novel methodological techniques used in health and disease conditions. This will include an in-depth look at cell culture and iPSCs, post-mortem studies, imaging and fluid biomarkers, genetics and transcriptomic data. In this review, we will discuss the advantages and limitations of these methods, highlighting the understanding these methods have brought the field on these cells communicative abilities, and the knowledge gaps that remain.
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Affiliation(s)
| | | | - Delphine Boche
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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39
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Mazzetti S, Barichella M, Giampietro F, Giana A, Calogero AM, Amadeo A, Palazzi N, Comincini A, Giaccone G, Bramerio M, Caronni S, Cereda V, Cereda E, Cappelletti G, Rolando C, Pezzoli G. Astrocytes expressing Vitamin D-activating enzyme identify Parkinson's disease. CNS Neurosci Ther 2022; 28:703-713. [PMID: 35166042 PMCID: PMC8981451 DOI: 10.1111/cns.13801] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 12/21/2021] [Accepted: 12/26/2021] [Indexed: 12/16/2022] Open
Abstract
Introduction Astrocytes are involved in Parkinson's disease (PD) where they could contribute to α‐Synuclein pathology but also to neuroprotection via α‐Synuclein clearance. The molecular signature underlying their dual role is still elusive. Given that vitamin D has been recently suggested to be protective in neurodegeneration, the aim of our study was to investigate astrocyte and neuron vitamin D pathway alterations and their correlation with α‐Synuclein aggregates (ie, oligomers and fibrils) in human brain obtained from PD patients. Methods The expression of vitamin D pathway components CYP27B1, CYP24A1, and VDR was examined in brains obtained from PD patients (Braak stage 6; n = 9) and control subjects (n = 4). We also exploited proximity ligation assay to identified toxic α‐Synuclein oligomers in human astrocytes. Results We found that vitamin D‐activating enzyme CYP27B1 identified a subpopulation of astrocytes exclusively in PD patients. CYP27B1 positive astrocytes could display neuroprotective features as they sequester α‐Synuclein oligomers and are associated with Lewy body negative neurons. Conclusion The presence of CYP27B1 astrocytes distinguishes PD patients and suggests their contribution to protect neurons and to ameliorate neuropathological traits.
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Affiliation(s)
- Samanta Mazzetti
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy.,Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy
| | - Michela Barichella
- Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy.,Parkinson Institute, ASST "G.Pini-CTO," Milan, Milan, Italy
| | | | - Angelica Giana
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy.,Parkinson Institute, ASST "G.Pini-CTO," Milan, Milan, Italy
| | | | - Alida Amadeo
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy.,Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy
| | - Nicola Palazzi
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | | | - Giorgio Giaccone
- Unit of Neuropathology and Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Manuela Bramerio
- S. C. Divisione Oncologia Falck and S. C. Divisione Anatomia Patologica, Ospedale Niguarda Ca' Granda, Milan, Italy
| | - Serena Caronni
- Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy.,Parkinson Institute, ASST "G.Pini-CTO," Milan, Milan, Italy
| | - Viviana Cereda
- Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy.,Parkinson Institute, ASST "G.Pini-CTO," Milan, Milan, Italy
| | - Emanuele Cereda
- Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Graziella Cappelletti
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy.,Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy
| | - Chiara Rolando
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - Gianni Pezzoli
- Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy.,Parkinson Institute, ASST "G.Pini-CTO," Milan, Milan, Italy
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40
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Aldabbagh Y, Islam A, Zhang W, Whiting P, Ali AB. Alzheimer’s Disease Enhanced Tonic Inhibition is Correlated With Upregulated Astrocyte GABA Transporter-3/4 in a Knock-In APP Mouse Model. Front Pharmacol 2022; 13:822499. [PMID: 35185574 PMCID: PMC8850407 DOI: 10.3389/fphar.2022.822499] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/12/2022] [Indexed: 11/25/2022] Open
Abstract
Cognitive decline is a major symptom in Alzheimer’s disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in APP knock-in mouse model of AD and whether this is correlated with changes in principal cell excitability. Using the APPNL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. We observed a higher expression of GAD67, an enzyme that catalyses GABA production, and GAT3/4 in reactive astrocytes labelled with GFAP, which correlated with an enhanced tonic inhibition in the CA1 and DG of 12–16 month-old APPNL-F/NL-F mice compared to the age-matched wild-type animals. Comparative neuroanatomy experiments performed using post-mortem brain tissue from human AD patients, age-matched to healthy controls, mirrored the results obtained using mice tissue. Blocking GAT3/4 associated tonic inhibition recorded in CA1 and DG principal cells resulted in an increased membrane input resistance, enhanced firing frequency and synaptic excitation in both wild-type and APPNL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APPNL-F/NL-F mice model. Our data suggest that an alteration in astrocyte GABA homeostasis is correlated with increased tonic inhibition in the hippocampus, which probably plays an important compensatory role in restoring AD-associated synaptic hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for AD
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Affiliation(s)
| | - Anam Islam
- UCL School of Pharmacy, London, United Kingdom
| | | | - Paul Whiting
- Alzheimer’s Research UK Drug Discovery Institute, Queen Square Institute of Neurology, London, United Kingdom
| | - Afia B. Ali
- UCL School of Pharmacy, London, United Kingdom
- *Correspondence: Afia B. Ali,
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41
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Bugiani M, Plug BC, Man JHK, Breur M, van der Knaap MS. Heterogeneity of white matter astrocytes in the human brain. Acta Neuropathol 2022; 143:159-177. [PMID: 34878591 DOI: 10.1007/s00401-021-02391-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/17/2021] [Accepted: 11/28/2021] [Indexed: 12/12/2022]
Abstract
Astrocytes regulate central nervous system development, maintain its homeostasis and orchestrate repair upon injury. Emerging evidence support functional specialization of astroglia, both between and within brain regions. Different subtypes of gray matter astrocytes have been identified, yet molecular and functional diversity of white matter astrocytes remains largely unexplored. Nonetheless, their important and diverse roles in maintaining white matter integrity and function are well recognized. Compelling evidence indicate that impairment of normal astrocytic function and their response to injury contribute to a wide variety of diseases, including white matter disorders. In this review, we highlight our current understanding of astrocyte heterogeneity in the white matter of the mammalian brain and how an interplay between developmental origins and local environmental cues contribute to astroglial diversification. In addition, we discuss whether, and if so, how, heterogeneous astrocytes could contribute to white matter function in health and disease and focus on the sparse human research data available. We highlight four leukodystrophies primarily due to astrocytic dysfunction, the so-called astrocytopathies. Insight into the role of astroglial heterogeneity in both healthy and diseased white matter may provide new avenues for therapies aimed at promoting repair and restoring normal white matter function.
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42
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Astrocytes in Neuropsychiatric Disorders: A Review of Postmortem Evidence. ADVANCES IN NEUROBIOLOGY 2021; 26:153-172. [PMID: 34888835 DOI: 10.1007/978-3-030-77375-5_8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glial cell types in the central nervous system (CNS) include microglia, oligodendrocytes and the most diverse type, astrocytes. Clinical and experimental evidence suggest critical roles for astrocytes in the pathogenesis of CNS disease. Here, we summarize the extensive morphological heterogeneity and physiological properties of different astrocyte subtypes. We review postmortem studies, discussing astrocyte-related changes found in the brain in subjects diagnosed with the neuropsychiatric disorders schizophrenia, major depressive disorder and bipolar disorder. Finally, we discuss the potential effects of psychotropic medication on these findings. In summary, postmortem studies highlight that the morphology of astrocytes and the expression of functionally important astrocyte markers are altered in the brain in neuropsychiatric disorders and may play a role in the pathophysiology of these serious mental illnesses.
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43
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Verkhratsky A, Parpura V, Li B, Scuderi C. Astrocytes: The Housekeepers and Guardians of the CNS. ADVANCES IN NEUROBIOLOGY 2021; 26:21-53. [PMID: 34888829 DOI: 10.1007/978-3-030-77375-5_2] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Astroglia are a diverse group of cells in the central nervous system. They are of the ectodermal, neuroepithelial origin and vary in morphology and function, yet, they can be collectively defined as cells having principle function to maintain homeostasis of the central nervous system at all levels of organisation, including homeostasis of ions, pH and neurotransmitters; supplying neurones with metabolic substrates; supporting oligodendrocytes and axons; regulating synaptogenesis, neurogenesis, and formation and maintenance of the blood-brain barrier; contributing to operation of the glymphatic system; and regulation of systemic homeostasis being central chemosensors for oxygen, CO2 and Na+. Their basic physiological features show a lack of electrical excitability (inapt to produce action potentials), but display instead a rather active excitability based on variations in cytosolic concentrations of Ca2+ and Na+. It is expression of neurotransmitter receptors, pumps and transporters at their plasmalemma, along with transports on the endoplasmic reticulum and mitochondria that exquisitely regulate the cytosolic levels of these ions, the fluctuation of which underlies most, if not all, astroglial homeostatic functions.
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Affiliation(s)
- Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
- Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
| | - Vladimir Parpura
- Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Baoman Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
| | - Caterina Scuderi
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy
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44
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Zhang X, Alnafisah RS, Hamoud ARA, Shukla R, Wen Z, McCullumsmith RE, O'Donovan SM. Role of Astrocytes in Major Neuropsychiatric Disorders. Neurochem Res 2021; 46:2715-2730. [PMID: 33411227 DOI: 10.1007/s11064-020-03212-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/17/2020] [Accepted: 12/21/2020] [Indexed: 12/30/2022]
Abstract
Astrocytes are the primary homeostatic cells of the central nervous system, essential for normal neuronal development and function, metabolism and response to injury and inflammation. Here, we review postmortem studies examining changes in astrocytes in subjects diagnosed with the neuropsychiatric disorders schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BPD). We discuss the astrocyte-related changes described in the brain in these disorders and the potential effects of psychotropic medication on these findings. Finally, we describe emerging tools that can be used to study the role of astrocytes in neuropsychiatric illness.
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Affiliation(s)
- Xiaolu Zhang
- Department of Neurosciences, University of Toledo College of Medicine, Block Health Science Building, 3000 Arlington Avenue, Toledo, OH, 43614, USA
| | - Rawan S Alnafisah
- Department of Neurosciences, University of Toledo College of Medicine, Block Health Science Building, 3000 Arlington Avenue, Toledo, OH, 43614, USA
| | - Abdul-Rizaq A Hamoud
- Department of Neurosciences, University of Toledo College of Medicine, Block Health Science Building, 3000 Arlington Avenue, Toledo, OH, 43614, USA
| | - Rammohan Shukla
- Department of Neurosciences, University of Toledo College of Medicine, Block Health Science Building, 3000 Arlington Avenue, Toledo, OH, 43614, USA
| | - Zhexing Wen
- Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Robert E McCullumsmith
- Department of Neurosciences, University of Toledo College of Medicine, Block Health Science Building, 3000 Arlington Avenue, Toledo, OH, 43614, USA
- Neurosciences Institute, ProMedica, Toledo, OH, USA
| | - Sinead M O'Donovan
- Department of Neurosciences, University of Toledo College of Medicine, Block Health Science Building, 3000 Arlington Avenue, Toledo, OH, 43614, USA.
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45
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Pivoriūnas A, Verkhratsky A. Astrocyte-Endotheliocyte Axis in the Regulation of the Blood-Brain Barrier. Neurochem Res 2021; 46:2538-2550. [PMID: 33961207 DOI: 10.1007/s11064-021-03338-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/18/2022]
Abstract
The evolution of blood-brain barrier paralleled centralisation of the nervous system: emergence of neuronal masses required control over composition of the interstitial fluids. The barriers were initially created by glial cells, which employed septate junctions to restrict paracellular diffusion in the invertebrates and tight junctions in some early vertebrates. The endothelial barrier, secured by tight and adherent junctions emerged in vertebrates and is common in mammals. Astrocytes form the parenchymal part of the blood-brain barrier and commutate with endothelial cells through secretion of growth factors, morphogens and extracellular vesicles. These secreted factors control the integrity of the blood-brain barrier through regulation of expression of tight junction proteins. The astrocyte-endotheliocyte communications are particularly important in various neurological diseases associated with impairments to the blood-brain barrier. Molecular mechanisms supporting astrocyte-endotheliocyte axis in health and disease are in need of detailed characterisation.
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Affiliation(s)
- Augustas Pivoriūnas
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, 01102, Vilnius, Lithuania.
| | - Alexei Verkhratsky
- Department of Stem Cell Biology, State Research Institute Centre for Innovative Medicine, 01102, Vilnius, Lithuania.
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK.
- Achucarro Centre for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain.
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46
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Preman P, TCW J, Calafate S, Snellinx A, Alfonso-Triguero M, Corthout N, Munck S, Thal DR, Goate AM, De Strooper B, Arranz AM. Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques. Mol Neurodegener 2021; 16:68. [PMID: 34563212 PMCID: PMC8467145 DOI: 10.1186/s13024-021-00487-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 08/21/2021] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. RESULTS To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background. CONCLUSIONS In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.
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Affiliation(s)
- Pranav Preman
- grid.511015.1VIB Center for Brain & Disease Research, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
| | - Julia TCW
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY USA ,grid.59734.3c0000 0001 0670 2351Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ,grid.59734.3c0000 0001 0670 2351Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Sara Calafate
- grid.511015.1VIB Center for Brain & Disease Research, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
| | - An Snellinx
- grid.511015.1VIB Center for Brain & Disease Research, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium
| | - Maria Alfonso-Triguero
- grid.427629.cAchucarro Basque Center for Neuroscience, Leioa, Spain ,grid.11480.3c0000000121671098Department of Neurosciences, Universidad del País Vasco (UPV/EHU), Leioa, Spain
| | - Nikky Corthout
- grid.511015.1VIB Center for Brain & Disease Research, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium ,VIB Bio Imaging Core, Campus Gasthuisberg, 3000 Leuven, Belgium
| | - Sebastian Munck
- grid.511015.1VIB Center for Brain & Disease Research, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium ,VIB Bio Imaging Core, Campus Gasthuisberg, 3000 Leuven, Belgium
| | - Dietmar Rudolf Thal
- grid.5596.f0000 0001 0668 7884Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), Department of Pathology, KU Leuven (University of Leuven), University Hospital Leuven, Leuven, Belgium
| | - Alison M Goate
- grid.59734.3c0000 0001 0670 2351Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY USA ,grid.59734.3c0000 0001 0670 2351Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA ,grid.59734.3c0000 0001 0670 2351Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Bart De Strooper
- grid.511015.1VIB Center for Brain & Disease Research, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium ,grid.83440.3b0000000121901201Dementia Research Institute, University College London, London, UK
| | - Amaia M Arranz
- grid.511015.1VIB Center for Brain & Disease Research, Leuven, Belgium ,grid.5596.f0000 0001 0668 7884Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium ,grid.427629.cAchucarro Basque Center for Neuroscience, Leioa, Spain ,grid.424810.b0000 0004 0467 2314Ikerbasque Basque Foundation for Science, Bilbao, Spain
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47
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Falcone C, McBride EL, Hopkins WD, Hof PR, Manger PR, Sherwood CC, Noctor SC, Martínez-Cerdeño V. Redefining varicose projection astrocytes in primates. Glia 2021; 70:145-154. [PMID: 34533866 DOI: 10.1002/glia.24093] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/02/2021] [Accepted: 09/02/2021] [Indexed: 01/14/2023]
Abstract
Varicose projection astrocytes (VP-As) are found in the cerebral cortex and have been described to be specific to humans and chimpanzees. To further examine the phylogenetic distribution of this cell type, we analyzed cortical tissue from several primates ranging from primitive primates to primates evolutionary closer to human such as apes. We specifically analyzed tissue from four strepsirrhine species, one tarsier, six species of platyrrhine monkeys, ten species of cercopithecoid monkeys, two hylobatid ape species, four to six cases each of chimpanzee, bonobo, gorilla, and orangutan, and thirteen human. We found that VP-As were present only in human and other apes (hominoids) and were absent in all other species. We showed that VP-As are localized to layer VI and the superficial white matter of the cortex. The presence of VP-As co-occured with interlaminar astrocytes that also had varicosities in their processes. Due to their location, their long tangential processes, and their irregular presence within species, we propose that VP-As are astrocytes that develop varicosities under specific conditions and that are not a distinct astrocyte type.
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Affiliation(s)
- Carmen Falcone
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California, USA.,Institute for Pediatric Regenerative Medicine and Shriners Hospitals, Sacramento, California, USA
| | - Erin L McBride
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California, USA.,Institute for Pediatric Regenerative Medicine and Shriners Hospitals, Sacramento, California, USA
| | - William D Hopkins
- Department of Comparative Medicine, Keeling Center for Comparative Medicine and Research, The University of Texas MD Anderson Cancer Center, Bastrop, Texas, USA
| | - Patrick R Hof
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Paul R Manger
- School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Chet C Sherwood
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
| | - Stephen C Noctor
- MIND Institute, UC Davis School of Medicine, Sacramento, California, USA.,Department of Psychiatry and Behavioral Sciences, UC Davis School of Medicine, Sacramento, California, USA
| | - Verónica Martínez-Cerdeño
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California, USA.,Institute for Pediatric Regenerative Medicine and Shriners Hospitals, Sacramento, California, USA.,MIND Institute, UC Davis School of Medicine, Sacramento, California, USA
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48
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Jurga AM, Paleczna M, Kadluczka J, Kuter KZ. Beyond the GFAP-Astrocyte Protein Markers in the Brain. Biomolecules 2021; 11:biom11091361. [PMID: 34572572 PMCID: PMC8468264 DOI: 10.3390/biom11091361] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022] Open
Abstract
The idea of central nervous system as one-man band favoring neurons is long gone. Now we all are aware that neurons and neuroglia are team players and constant communication between those various cell types is essential to maintain functional efficiency and a quick response to danger. Here, we summarize and discuss known and new markers of astroglial multiple functions, their natural heterogeneity, cellular interactions, aging and disease-induced dysfunctions. This review is focused on newly reported facts regarding astrocytes, which are beyond the old stereotypes. We present an up-to-date list of marker proteins used to identify a broad spectrum of astroglial phenotypes related to the various physiological and pathological nervous system conditions. The aim of this review is to help choose markers that are well-tailored for specific needs of further experimental studies, precisely recognizing differential glial phenotypes, or for diagnostic purposes. We hope it will help to categorize the functional and structural diversity of the astroglial population and ease a clear readout of future experimental results.
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49
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Hart CG, Karimi-Abdolrezaee S. Recent insights on astrocyte mechanisms in CNS homeostasis, pathology, and repair. J Neurosci Res 2021; 99:2427-2462. [PMID: 34259342 DOI: 10.1002/jnr.24922] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/06/2021] [Accepted: 06/24/2021] [Indexed: 12/20/2022]
Abstract
Astrocytes play essential roles in development, homeostasis, injury, and repair of the central nervous system (CNS). Their development is tightly regulated by distinct spatial and temporal cues during embryogenesis and into adulthood throughout the CNS. Astrocytes have several important responsibilities such as regulating blood flow and permeability of the blood-CNS barrier, glucose metabolism and storage, synapse formation and function, and axon myelination. In CNS pathologies, astrocytes also play critical parts in both injury and repair mechanisms. Upon injury, they undergo a robust phenotypic shift known as "reactive astrogliosis," which results in both constructive and deleterious outcomes. Astrocyte activation and migration at the site of injury provides an early defense mechanism to minimize the extent of injury by enveloping the lesion area. However, astrogliosis also contributes to the inhibitory microenvironment of CNS injury and potentiate secondary injury mechanisms, such as inflammation, oxidative stress, and glutamate excitotoxicity, which facilitate neurodegeneration in CNS pathologies. Intriguingly, reactive astrocytes are increasingly a focus in current therapeutic strategies as their activation can be modulated toward a neuroprotective and reparative phenotype. This review will discuss recent advancements in knowledge regarding the development and role of astrocytes in the healthy and pathological CNS. We will also review how astrocytes have been genetically modified to optimize their reparative potential after injury, and how they may be transdifferentiated into neurons and oligodendrocytes to promote repair after CNS injury and neurodegeneration.
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Affiliation(s)
- Christopher G Hart
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada
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50
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Lim D, Semyanov A, Genazzani A, Verkhratsky A. Calcium signaling in neuroglia. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 362:1-53. [PMID: 34253292 DOI: 10.1016/bs.ircmb.2021.01.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glial cells exploit calcium (Ca2+) signals to perceive the information about the activity of the nervous tissue and the tissue environment to translate this information into an array of homeostatic, signaling and defensive reactions. Astrocytes, the best studied glial cells, use several Ca2+ signaling generation pathways that include Ca2+ entry through plasma membrane, release from endoplasmic reticulum (ER) and from mitochondria. Activation of metabotropic receptors on the plasma membrane of glial cells is coupled to an enzymatic cascade in which a second messenger, InsP3 is generated thus activating intracellular Ca2+ release channels in the ER endomembrane. Astrocytes also possess store-operated Ca2+ entry and express several ligand-gated Ca2+ channels. In vivo astrocytes generate heterogeneous Ca2+ signals, which are short and frequent in distal processes, but large and relatively rare in soma. In response to neuronal activity intracellular and inter-cellular astrocytic Ca2+ waves can be produced. Astrocytic Ca2+ signals are involved in secretion, they regulate ion transport across cell membranes, and are contributing to cell morphological plasticity. Therefore, astrocytic Ca2+ signals are linked to fundamental functions of the central nervous system ranging from synaptic transmission to behavior. In oligodendrocytes, Ca2+ signals are generated by plasmalemmal Ca2+ influx, or by release from intracellular stores, or by combination of both. Microglial cells exploit Ca2+ permeable ionotropic purinergic receptors and transient receptor potential channels as well as ER Ca2+ release. In this contribution, basic morphology of glial cells, glial Ca2+ signaling toolkit, intracellular Ca2+ signals and Ca2+-regulated functions are discussed with focus on astrocytes.
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Affiliation(s)
- Dmitry Lim
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy.
| | - Alexey Semyanov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Faculty of Biology, Moscow State University, Moscow, Russia; Sechenov First Moscow State Medical University, Moscow, Russia
| | - Armando Genazzani
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Alexei Verkhratsky
- Sechenov First Moscow State Medical University, Moscow, Russia; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom; Achucarro Centre for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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