Glial fibrillary acidic protein (GFAP) is the hallmark intermediate filament (IF; also known as nanofilament) protein in astrocytes, a main type of glial cells in the central nervous system (CNS). ...Astrocytes have a range of control and homeostatic functions in health and disease. Astrocytes assume a reactive phenotype in acute CNS trauma, ischemia, and in neurodegenerative diseases. This coincides with an upregulation and rearrangement of the IFs, which form a highly complex system composed of GFAP (10 isoforms), vimentin, synemin, and nestin. We begin to unravel the function of the IF system of astrocytes and in this review we discuss its role as an important crisis-command center coordinating cell responses in situations connected to cellular stress, which is a central component of many neurological diseases.
SummaryType III intermediate filament (IF) proteins assemble into cytoplasmic homopolymeric and heteropolymeric filaments with other type III and some type IV IFs. These highly dynamic structures ...form an integral component of the cytoskeleton of muscle, brain, and mesenchymal cells. Here, we review the current ideas on the role of type III IFs in health and disease. It turns out that they not only offer resilience to mechanical strains, but, most importantly, they facilitate very efficiently the integration of cell structure and function, thus providing the necessary scaffolds for optimal cellular responses upon biochemical stresses and protecting against cell death, disease, and aging.
Glia are essential for brain functioning during development and in the adult brain. Here, we discuss the various roles of both microglia and astrocytes, and their interactions during brain ...development. Although both cells are fundamentally different in origin and function, they often affect the same developmental processes such as neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis and synaptic pruning. Due to their important instructive roles in these processes, dysfunction of microglia or astrocytes during brain development could contribute to neurodevelopmental disorders and potentially even late-onset neuropathology. A better understanding of the origin, differentiation process and developmental functions of microglia and astrocytes will help to fully appreciate their role both in the developing as well as in the adult brain, in health and disease.
Amyloid plaques in Alzheimer's disease (AD) mice are surrounded by activated microglia. The functional role of microglia activation in AD is not well understood; both detrimental and beneficial ...effects on AD progression have been reported. Here we show that the population of activated microglia in the cortex of the APPswe/PS1dE9 mouse AD model is divided into a CD11c-positive and a CD11c-negative subpopulation.
Cd11c transcript levels and number of CD11c-positive microglia increase sharply when plaques start to occur and both parameters continue to rise in parallel with the age-related increasing plaque load. CD11c cells are localized near plaques at all stages of the disease development and constitute 23% of all activated microglia. No differences between these two populations were found in terms of proliferation, immunostaining intensity of Iba1, MHC class II, CD45, or immunoproteasome subunit LMP7/β5i. Comparison of the transcriptome of isolated CD11c-positive and CD11c-negative microglia from the cortex of aged APPswe/PS1dE9 with WT microglia showed that gene expression changes had a similar general pattern. However, a differential expression was found for genes involved in immune signaling (Il6, S100a8/Mrp8, S100a9/Mrp14, Spp1, Igf1), lysosome activation, and carbohydrate- and cholesterol/lipid-metabolism (Apoe). In addition, the increased expression of Gpnmb/DC-HIL, Tm7sf4/DC-STAMP, and Gp49a/Lilrb4, suggests a suppressive/tolerizing influence of CD11c cells.
We show that amyloid plaques in the APP/PS1 model are associated with two distinct populations of activated microglia: CD11c-positive and CD11c-negative cells. Our findings imply that CD11c-positive microglia can potentially counteract amyloid deposition via increased Aβ-uptake and degradation, and by containing the inflammatory response.
•Activated microglia near amyloid plaques are composed of CD11c-negative and CD11c-positive cells.•Both populations express the same profile of markers and their levels of proliferation do not differ.•Gene expression patterns indicate a suppressive/tolerizing effect of immune signaling by CD11c-cells.•Gene expression patterns indicate enhanced capacity for uptake and lysosomal degradation of Aβ by CD11c-cells.
Alzheimer's disease is the main cause of dementia in the elderly and begins with a subtle decline in episodic memory followed by a more general decline in overall cognitive abilities. Though the ...exact trigger for this cascade of events remains unknown the presence of the misfolded amyloid-beta protein triggers reactive gliosis, a prominent neuropathological feature in the brains of Alzheimer's patients. The cytoskeletal and morphological changes of astrogliosis are its evident features, while changes in oxidative stress defense, cholesterol metabolism, and gene transcription programs are less manifest. However, these latter molecular changes may underlie a disruption in homeostatic regulation that keeps the brain environment balanced. Astrocytes in Alzheimer's disease show changes in glutamate and GABA signaling and recycling, potassium buffering, and in cholinergic, purinergic, and calcium signaling. Ultimately the dysregulation of homeostasis maintained by astrocytes can have grave consequences for the stability of microcircuits within key brain regions. Specifically, altered inhibition influenced by astrocytes can lead to local circuit imbalance with farther reaching consequences for the functioning of larger neuronal networks. Healthy astrocytes have a role in maintaining and modulating normal neuronal communication, synaptic physiology and energy metabolism, astrogliosis interferes with these functions. This review considers the molecular and functional changes occurring during astrogliosis in Alzheimer's disease, and proposes that astrocytes are key players in the development of dementia.
Abstract Astrocytes and microglia become reactive in many neurological disorders resulting in phenotypic and functional alterations. Both cell types might also display functional changes during ...normal aging. To identify gene signatures and changes in basal cellular functions of astrocytes and microglia in relation to aging, we isolated viable astrocytes and microglia from young adult and aged mouse cortices and determined their gene expression profile. Aged astrocytes, compared with young astrocytes, showed an increased inflammatory phenotype and increased ‘zinc ion binding.’ Young astrocytes showed higher expression of genes involved in ‘neuronal differentiation’ and hemoglobin synthesis. Astrocyte expression of genes involved in neuronal signaling remains high throughout age. Aged microglia had higher expression of genes involved in ‘vesicle release,’ ‘zinc ion binding,’ and genes within the tumor necrosis factor-ligand family and young microglia had increased transcript levels of C-C motif chemokines. These data provide a transcriptome database of cell-type enriched genes of astrocytes and microglia from adult mice and give insight into the differential gene signature of astrocytes and microglia in relation to normal aging.
Abstract
Diffuse midline glioma (DMG), formerly called diffuse intrinsic pontine glioma (DIPG), is a high-grade malignant pediatric brain tumor with a near-zero survival rate. To date, only radiation ...therapy provides marginal survival benefit; however, the median survival time remains less than a year. Historically, the infiltrative nature and sensitive location of the tumor rendered surgical removal and biopsies difficult and subsequently resulted in limited knowledge of the disease, as only post-mortem tissue was available. Therefore, clinical decision-making was based upon experience with the more frequent and histologically similar adult glioblastoma (GBM). Recent advances in tissue acquisition and molecular profiling revealed that DMG and GBM are distinct disease entities, with separate tissue characteristics and genetic profiles. DMG is characterized by heterogeneous tumor tissue often paired with an intact blood–brain barrier, possibly explaining its resistance to chemotherapy. Additional profiling shed a light on the origin of the disease and the influence of several mutations such as a highly recurring K27M mutation in histone H3 on its tumorigenesis. Furthermore, early evidence suggests that DMG has a unique immune microenvironment, characterized by low levels of immune cell infiltration, inflammation, and immunosuppression that may impact disease development and outcome. Within the tumor microenvironment of GBM, tumor-associated microglia/macrophages (TAMs) play a large role in tumor development. Interestingly, TAMs in DMG display distinct features and have low immune activation in comparison to other pediatric gliomas. Although TAMs have been investigated substantially in GBM over the last years, this has not been the case for DMG due to the lack of tissue for research. Bit by bit, studies are exploring the TAM–glioma crosstalk to identify what factors within the DMG microenvironment play a role in the recruitment and polarization of TAMs. Although more research into the immune microenvironment is warranted, there is evidence that targeting or stimulating TAMs and their factors provide a potential treatment option for DMG. In this review, we provide insight into the current status of DMG research, assess the knowledge of the immune microenvironment in DMG and GBM, and present recent findings and therapeutic opportunities surrounding the TAM–glioma crosstalk.
Abstract In Alzheimer's disease (AD), amyloid plaques are surrounded by reactive astrocytes with an increased expression of intermediate filaments including glial fibrillary acidic protein (GFAP). ...Different GFAP isoforms have been identified that are differentially expressed by specific subpopulations of astrocytes and that impose different properties to the intermediate filament network. We studied transcript levels and protein expression patterns of all known GFAP isoforms in human hippocampal AD tissue at different stages of the disease. Ten different transcripts for GFAP isoforms were detected at different abundancies. Transcript levels of most isoforms increased with AD progression. GFAPδ-immunopositive astrocytes were observed in subgranular zone, hilus, and stratum–lacunosum–moleculare. GFAPδ-positive cells also stained for GFAPα. In AD donors, astrocytes near plaques displayed increased staining of both GFAPα and GFAPδ. The reading-frame–shifted isoform, GFAP+1 , staining was confined to a subset of astrocytes with long processes, and their number increased in the course of AD. In conclusion, the various GFAP isoforms show differential transcript levels and are upregulated in a concerted manner in AD. The GFAP+1 isoform defines a unique subset of astrocytes, with numbers increasing with AD progression. These data indicate the need for future exploration of underlying mechanisms concerning the functions of GFAPδ and GFAP+1 isoforms in astrocytes and their possible role in AD pathology.
To report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies.
From January 2012 to March 2017, we recruited 451 patients with ...suspected neurological autoimmune disease at the Catholic University of Rome. Patients' serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections.
Serum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells.
GFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases.
Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal ...lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease.
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