Faculty Bibliography
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87
Reactive astrocyte nomenclature, definitions, and future directions
Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.
PMID: 33589835
ISSN: 1546-1726
CID: 4786612
Astrocyte-immune cell interactions in physiology and pathology
Astrocytes play both physiological and pathological roles in maintaining central nervous system (CNS) function. Here, we review the varied functions of astrocytes and how these might change in subsets of reactive astrocytes. We review the current understanding of astrocyte interactions with microglia and the vasculature and protective barriers in the central nervous system as well as highlight recent insights into physiologic and reactive astrocyte sub-states identified by transcriptional profiling. Our goal is to stimulate inquiry into how these molecular identifiers link to specific functional changes in astrocytes and to define the implications of these heterogeneous molecular and functional changes in brain function and pathology. Defining these complex interactions has the potential to yield new therapies in CNS injury, infection, and disease.
PMID: 33567261
ISSN: 1097-4180
CID: 4799792
Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency
Aberrant aggregation of RNA binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by progranulin haploinsufficiency1,2. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA-sequencing (snRNA-seq) to show that progranulin deficiency promotes microglial transition from a homeostatic to disease-specific state that causes endolysosomal dysfunction and neurodegeneration. These defects persist even when Grn-/- microglia are cultured ex vivo. In addition, snRNA-seq reveals selective loss of excitatory neurons at disease end-stage, characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn-/- microglia is sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deleting C1qa and C3 mitigates microglial toxicity, and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.
PMID: 32866962
ISSN: 1476-4687
CID: 4615342
An Overview of Astrocyte Responses in Genetically Induced Alzheimer's Disease Mouse Models
Alzheimer's disease (AD) is the most common form of dementia. Despite many years of intense research, there is currently still no effective treatment. Multiple cell types contribute to disease pathogenesis, with an increasing body of data pointing to the active participation of astrocytes. Astrocytes play a pivotal role in the physiology and metabolic functions of neurons and other cells in the central nervous system. Because of their interactions with other cell types, astrocyte functions must be understood in their biologic context, thus many studies have used mouse models, of which there are over 190 available for AD research. However, none appear able to fully recapitulate the many functional changes in astrocytes reported in human AD brains. Our review summarizes the observations of astrocyte biology noted in mouse models of familial and sporadic AD. The limitations of AD mouse models will be discussed and current attempts to overcome these disadvantages will be described. With increasing understanding of the non-neuronal contributions to disease, the development of new methods and models will provide further insights and address important questions regarding the roles of astrocytes and other non-neuronal cells in AD pathophysiology. The next decade will prove to be full of exciting opportunities to address this devastating disease.
PMCID:7694249
PMID: 33158189
ISSN: 2073-4409
CID: 4681332
Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime?
Microglia-astrocyte interactions represent a delicate balance affecting neural cell functions in health and disease. Tightly controlled to maintain homeostasis during physiological conditions, rapid and prolonged departures during disease, infection, and following trauma drive multiple outcomes: both beneficial and detrimental. Recent sequencing studies at the bulk and single-cell level in humans and rodents provide new insight into microglia-astrocyte communication in homeostasis and disease. However, the complex changing ways these two cell types functionally interact has been a barrier to understanding disease initiation, progression, and disease mechanisms. Single cell sequencing is providing new insights; however, many questions remain. Here, we discuss how to bridge transcriptional states to specific functions so we can develop therapies to mediate negative effects of altered microglia-astrocyte interactions.
PMID: 32819809
ISSN: 1471-4981
CID: 4581452
CD49f Is a Novel Marker of Functional and Reactive Human iPSC-Derived Astrocytes
New methods for investigating human astrocytes are urgently needed, given their critical role in the central nervous system. Here we show that CD49f is a novel marker for human astrocytes, expressed in fetal and adult brains from healthy and diseased individuals. CD49f can be used to purify fetal astrocytes and human induced pluripotent stem cell (hiPSC)-derived astrocytes. We provide single-cell and bulk transcriptome analyses of CD49f+ hiPSC-astrocytes and demonstrate that they perform key astrocytic functions in vitro, including trophic support of neurons, glutamate uptake, and phagocytosis. Notably, CD49f+ hiPSC-astrocytes respond to inflammatory stimuli, acquiring an A1-like reactive state, in which they display impaired phagocytosis and glutamate uptake and fail to support neuronal maturation. Most importantly, we show that conditioned medium from human reactive A1-like astrocytes is toxic to human and rodent neurons. CD49f+ hiPSC-astrocytes are thus a valuable resource for investigating human astrocyte function and dysfunction in health and disease.
PMID: 32485136
ISSN: 1097-4199
CID: 4480952
Generating Cell Type-Specific Protein Signatures from Non-symptomatic and Diseased Tissues
Here we demonstrate a technique to generate proteomic signatures of specific cell types within heterogeneous populations. While our method is broadly applicable across biological systems, we have limited the current work to study neural cell types isolated from human, post-mortem Alzheimer's disease (AD) and aged-matched non-symptomatic (NS) brains. Motivating the need for this tool, we conducted an initial meta-analysis of current, human AD proteomics studies. While the results broadly corroborated major neurodegenerative disease hypotheses, cell type-specific predictions were limited. By adapting our Formaldehyde-fixed Intracellular Target-Sorted Antigen Retrieval (FITSAR) method for proteomics and applying this technique to characterize AD and NS brains, we generated enriched neuron and astrocyte proteomic profiles for a sample set of donors (available at www.fitsarpro.appspot.com). Results showed the feasibility for using FITSAR to evaluate cell-type specific hypotheses. Our overall methodological approach provides an accessible platform to determine protein presence in specific cell types and emphasizes the need for protein-compatible techniques to resolve systems complicated by cellular heterogeneity.
PMID: 32303872
ISSN: 1573-9686
CID: 4401842
Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model
Reactive astrocytes have been implicated in the pathogenesis of neurodegenerative diseases, including a non-cell autonomous effect on motor neuron survival in ALS. We previously defined a mechanism by which microglia release three factors, IL-1α, TNFα, and C1q, to induce neurotoxic astrocytes. Here we report that knocking out these three factors markedly extends survival in the SOD1G93A ALS mouse model, providing evidence for gliosis as a potential ALS therapeutic target.
PMID: 32719333
ISSN: 2041-1723
CID: 4552632
How Support of Early Career Researchers Can Reset Science in the Post-COVID19 World
The COVID19 crisis has magnified the issues plaguing academic science, but it has also provided the scientific establishment with an unprecedented opportunity to reset. Shoring up the foundation of academic science will require a concerted effort between funding agencies, universities, and the public to rethink how we support scientists, with a special emphasis on early career researchers.
PMCID:7291965
PMID: 32533917
ISSN: 1097-4172
CID: 4496582
Neurotoxic Reactive Astrocytes Drive Neuronal Death after Retinal Injury
Glaucoma is a neurodegenerative disease that features the death of retinal ganglion cells (RGCs) in the retina, often as a result of prolonged increases in intraocular pressure. We show that preventing the formation of neuroinflammatory reactive astrocytes prevents the death of RGCs normally seen in a mouse model of glaucoma. Furthermore, we show that these spared RGCs are electrophysiologically functional and thus still have potential value for the function and regeneration of the retina. Finally, we demonstrate that the death of RGCs depends on a combination of both an injury to the neurons and the presence of reactive astrocytes, suggesting a model that may explain why reactive astrocytes are toxic only in some circumstances. Altogether, these findings highlight reactive astrocytes as drivers of RGC death in a chronic neurodegenerative disease of the eye.
PMID: 32579912
ISSN: 2211-1247
CID: 4514532
