Shane A Liddelow

• BBiomedSc., BSc(Hons), PhD
• Professor (Associate) at NYU Grossman School of Medicine

Innate immune memory, in which prior immune stimuli can "train" certain immune cells to respond more aggressively to subsequent challenges, is crucial for immune system plasticity in disease. Lee et al. [1] recently described a similar kind of immune memory state in astrocytes which they termed "epigenetic memory astrocytes". The discovery of astro...

Glaucomatous optic neuropathy, or glaucoma, is the world’s primary cause of irreversible blindness. Glaucoma is comorbid with other neurodegenerative diseases, but how it might impact the environment of the full central nervous system to increase neurodegenerative vulnerability is unknown. Two neurodegenerative events occur early in the optic nerve...

Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor how they contribute to neuronal dysfunction and disease risk as organisms age. Here, we examine the transcriptional, cell biology, and functional differences in astrocytes across normal aging. Astrocytes at baseline are h...

The relative ease of generation and proliferation of omics datasets has moved considerably faster than the effective dissemination of these data to the scientific community. Despite advancements in making raw data publicly available, many researchers struggle with data analysis and integration. We propose sharing analyzed data through user‐friendly...

The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in...

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and a...

Single-cell or single-nucleus transcriptomics is a powerful tool for identifying cell types and cell states. However, hypotheses derived from these assays, including gene expression information, require validation, and their functional relevance needs to be established. The choice of validation depends on numerous factors. Here, we present types of...

Over the past decade, single-cell genomics technologies have allowed scalable profiling of cell-type-specific features, which has substantially increased our ability to study cellular diversity and transcriptional programs in heterogeneous tissues. Yet our understanding of mechanisms of gene regulation or the rules that govern interactions between...

Single-cell and single-nucleus genomic approaches can provide unbiased and multimodal insights. Here, we discuss what constitutes a molecular cell atlas and how to leverage single-cell omics data to generate hypotheses and gain insights into cell transitions in development and disease of the nervous system. We share points of reflection on what to...

Alzheimer’s disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of sex chromosomes and gonads in demyelination and AD. In a mouse model of demyelination, we identified the roles of sex chromosomes and gonads in modifying...

Astrocyte morphology in vivo is heterogeneous across different subtypes and dynamically changes in response to various stimuli. However, several questions on the mechanistic links between shape and function remain unanswered. Here, we developed an efficient protocol to generate pure populations of morphologically distinct human astrocytes in vitro,...

Perinatal white matter injury (WMI) is the leading cause of long‐term neurological morbidity in infants born preterm. Neuroinflammation during a critical window of early brain development plays a key role in WMI disease pathogenesis. The mechanisms linking inflammation with the long‐term myelination failure that characterizes WMI, however, remain u...

Persistent central nervous system (CNS) immune dysregulation and consequent dysfunction of multiple neural cell types is central to the neurobiological underpinnings of a cognitive impairment syndrome that can occur following traditional cancer therapies or certain infections. Immunotherapies have revolutionized cancer care for many tumor types, bu...

In addition to their many functions in the healthy central nervous system (CNS), astrocytes respond to CNS damage and disease through a process called "reactivity." Recent evidence reveals that astrocyte reactivity is a heterogeneous spectrum of potential changes that occur in a context-specific manner. These changes are determined by diverse signa...

Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and ast...

Astrocytes are a heterogeneous population of central nervous system glial cells that respond to pathological insults and injury by undergoing a transformation called “reactivity.” Reactive astrocytes exhibit distinct and context‐dependent cellular, molecular, and functional state changes that can either support or disturb tissue homeostasis. We rec...

Astrocytes undergo robust gene expression changes in response to a variety of perturbations, including ischemic injury. How these transitions are affected by time, and how heterogeneous and spatially distinct various reactive astrocyte populations are, remain unclear. To address these questions, we performed spatial transcriptomics as well as singl...

Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and ast...

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional ret...

Demyelination occurs in aging and associated diseases, including Alzheimer’s disease. Several of these diseases exhibit sex differences in prevalence and severity. Biological sex primarily stems from sex chromosomes and gonads releasing sex hormones. To dissect mechanisms underlying sex differences in demyelination of aging brains, we constructed a...

Macroglia (astrocytes and oligodendrocytes) are required for normal development and function of the central nervous system, yet many questions remain about their emergence during the development of the brain and spinal cord. Here we used single-cell/single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) to analyze over 298,000 cells and nuclei during...

Locomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific features during development. Using sin...

Single-cell RNA sequencing is a new frontier across all biology, particularly in neuroscience. While powerful for answering numerous neuroscience questions, limitations in sample input size, and initial capital outlay can exclude some researchers from its application. Here, we tested a recently introduced method for scRNAseq across diverse scales a...

Despite advances in uncovering the mechanisms that underlie neuroinflammation and neurodegenerative disease, therapies that prevent neuronal loss remain elusive. Targeting of disease-defining markers in conditions such as Alzheimer disease (amyloid-β and tau) or Parkinson disease (α-synuclein) has been met with limited success, suggesting that thes...

Astrocytes are a highly abundant glial cell type that perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogenous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important ana...

Introduction: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease...

Astrocytes and microglia are central players in a myriad of processes in the healthy and diseased brain, ranging from metabolism to immunity. The crosstalk between these two cell types contributes to pathology in many if not all neuroinflammatory and neurodegenerative diseases. Recent advancements in integrative multimodal sequencing techniques hav...

Locomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally-distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific molecular features during development....

Astrocytes can have helpful or harmful effects on neuron health and brain function in disease. While they normally provide trophic support to neurons during development and normal functioning, in response to many stimuli their heterogeneous ‘reactive’ responses can alter these functions drastically. Changes in astrocyte function depends on their ‘r...

The role of reactive astrocytes in perinatal white matter injury (WMI) is unclear. In a mouse model of WMI, we provide evidence that impairing the formation of a C3-expressing neuroinflammatory reactive astrocyte sub-state rescues myelination and behavioral deficits. We further demonstrate the presence of C3-expressing reactive astrocytes in human...

Introduction: The inositol polyphosphate-5-phosphatase D (INPP5D) gene encodes a dual-specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. Single nucleotide polymorphisms in INPP5D impact risk for developing late onset sporadic Alzheimer's disease (LOAD). Methods: To assess the consequences of inducible Inpp5d...

Studies of the choroid plexuses lag behind those of, the more widely known, blood brain barrier in spite of a much longer history. This review has two overall aims. The first is to outline longstanding areas of research where there are unanswered questions, such as control of cerebrospinal fluid (CSF) secretion and blood flow. The second part revie...

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapie...

COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective mi...

Astrocytes respond to injury, infection, and inflammation in the central nervous system by acquiring reactive states in which they may become dysfunctional and contribute to disease pathology. A sub-state of reactive astrocytes induced by proinflammatory factors TNF, IL-1α, and C1q (“TIC”) has been implicated in many neurodegenerative diseases as a...

The dual specificity lipid/protein phosphatase SHIP1 (encoded by the INPP5D gene) is enriched in myeloid cells. Single nucleotide polymorphisms (SNPs) in INPP5D coding and non-coding regions impact risk for developing late onset sporadic Alzheimer’s disease (LOAD). We present pathological analyses with spatial transcriptomics of mice with tamoxifen...

Resolving glial contributions to Alzheimer’s disease (AD) is necessary because changes in neuronal function, such as reduced synaptic density, altered electrophysiological properties, and degeneration, are not entirely cell autonomous. To improve understanding of transcriptomic heterogeneity in glia during AD, we used single-nuclei RNA sequencing (...

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and...

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer...

During neurogenesis, mitotic progenitor cells lining the ventricles of the embryonic mouse brain undergo their final rounds of cell division, giving rise to a wide spectrum of postmitotic neurons and glia 1,2 . The link between developmental lineage and cell-type diversity remains an open question. Here we used massively parallel tagging of progeni...

Central nervous system macroglia (astrocytes and oligodendrocytes) are required for normal brain development and function, and are among the last cells to emerge during neurodevelopment. Many questions remain about their emergence in the brain and spinal cord, including how early glial fates are specified during development or differen- tiation, an...

Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease1–6. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor5,6. Notably, instead of a protein, saturated lipids contained in APOE and APOJ...

Astrocytes undergo an inflammatory transition after infections, acute injuries and chronic neurodegenerative diseases. How this transition is affected by time and sex, its heterogeneity at the single-cell level and how sub-states are spatially distributed in the brain remains unclear. In this study, we investigated transcriptome changes of mouse co...

Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer's disease (AD) have primarily focused on targeting antibodies to amyloid β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic...

Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer's disease (AD) have primarily focused on targeting antibodies to amyloid β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic...

Philip Hasel and Shane Liddelow introduce astrocytes - glial cells that help to maintain the homeostasis of the central nervous system during development, normal physiology, and aging.

Microbiome-induced interferon signaling through gut-derived natural killer cells is integral to minimize peripheral inflammatory responses in the brain and spinal cord. In a recent issue of Nature, Sanmarco, Wheeler, et al. define how interferon signaling induces LAMP1⁺TRAIL⁺ astrocytes, which cause death of inflammatory T cells, mitigating degener...

Apolipoprotein E (APOE) is the most abundant apolipoprotein in the brain, where it is primarily expressed and secreted by astrocytes and microglia. APOE seems to exert immunomodulatory effects in an isoform-dependent way, and a new study indicates that the APOE isoform dictates the glycosylation state and secretion of this apolipoprotein.

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...

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 t...

Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto‐immune demyelinating disorder. The precise role of microglia, parenchymal central nervous system (CNS) macrophages, during demyelination, and the relative contributions of peripheral macrophages are incompletely under...

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...

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 metabo...

Regulating gene expression at the protein level is becoming increasingly important for answering basic questions in neurobiology. Several techniques using destabilizing domains (DD) on transgenes, which can be activated or deactivated by specific drugs, have been developed to achieve this goal. A DD from bacterial dihydrofolate reductase bound and...

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 (...

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 st...

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 ma...

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 spe...

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 t...

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...

Oxidative stress is an imbalance in the production of reactive oxygen species and the ability to remove or detoxify these molecules, which causes cellular damage. Leveraging novel sequencing methods and high-throughput screens leads to the discovery of possible new therapies.

Phagocytosis by glial cells is essential to regulate brain function during development and disease. Given recent interest in using amyloid β (Aβ)-targeted antibodies as a therapy for patients with Alzheimer's disease, removal of Aβ by phagocytosis is likely protective early in Alzheimer's disease, but remains poorly understood. Impaired phagocytic...

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer...

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activ...

Altered metabolic function is common in stressed immune cells, but alteration in brain microglia during neurodegeneration is not understood. In this issue, Baik et al. (2019) provide insight into microglial metabolism. They demonstrate a switch from oxidative phosphorylation to glycolysis following interaction with amyloid beta acutely, and breakdo...

Astrocytes play a central role in the central nervous system (CNS), maintaining brain homeostasis, providing metabolic support to neurons, regulating connectivity of neural circuits, and controlling blood flow as an integral part of the blood-brain barrier. They have been increasingly implicated in the mechanisms of neurodegenerative diseases, prom...

Astrogliosis and activation of microglia are hallmarks of prion diseases in humans and animals. Both were viewed to be rather independent events in disease pathophysiology, with proinflammatory microglia considered to be the potential neurotoxic species at late disease stages. Recent investigations have provided substantial evidence that a proinfla...

Astrocytes are emerging as causal or modulating factors in diverse neurological disorders. Two papers published in Nature Neuroscience in 2007 revealed astrocytes as causally contributing to motor neuron loss in amyotrophic lateral sclerosis, thereby challenging the longstanding neuron-centric view of neurodegenerative disease.

Astrocytes are essential for CNS health, regulating homeostasis, metabolism, and synaptic transmission. In addition to these and many other physiological roles, the pathological impact of astrocytes (“reactive astrocytes”) in acute trauma and chronic disease like Alzheimer's disease (AD) is well established. Growing evidence supports a fundamental...

The slow, continuous, devastating march of Alzheimer's disease continues to move across the globe. As a society, we are at a loss for options to treat or reverse the death of neurons—the final, apparently inescapable, hallmark of the disease. A continued focus on these dying neurons has taught us much about the disease but with no knowledge‐based e...

Glial cells serve as fundamental regulators of the central nervous system in development, homeostasis, and disease. Discoveries into the function of these cells have fueled excitement in glial research, with enthusiastic researchers addressing fundamental questions about glial biology and producing new scientific tools for the community. Here, we o...

Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mou...

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergist...

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults, and plays a critical role in brain health and disease. We report that the core clock protein BMAL1 regulates astrogliosis in a synergistic manner...

Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1...

The decline of cognitive function occurs with aging, but the mechanisms responsible are unknown. Astrocytes instruct the formation, maturation, and elimination of synapses, and impairment of these functions has been implicated in many diseases. These findings raise the question of whether astrocyte dysfunction could contribute to cognitive decline...

Call to action The developing brain initially makes more synapses than it needs. With further development, excess synapses are pruned away, leaving mature circuits. Synapses can be eliminated by microglia, which engulf and destroy them. Vainchtein et al. found that the microglia are called into action by astrocytes, supportive cells on which neuron...

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergist...

Macrophages and other immune cells are increasingly recognized to have unique and nontraditional functions in various tissues of the body. In a recent issue of Nature Medicine, Pirzgalska et al. [1] characterized a unique set of tissue-specialized macrophages that modulate the connection between the nervous system and subcutaneous fat.

The blood-brain barriers of the central nervous system (CNS) provide a great deal of protection to the brain and spinal cord by blocking penetration of harmful molecules from the peripheral bloodstream. This article is protected by copyright. All rights reserved.

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms¹. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generatin...

Cells called astrocytes promote and maintain neuronal function. The discovery that astrocytes vary in their gene expression, protein levels, cellular structure and function suggests that they are specialized to support distinct circuits.

Astrocytes constitute approximately 30% of the cells in the mammalian central nervous system (CNS). They are integral to brain and spinal-cord physiology and perform many functions important for normal neuronal development, synapse formation, and proper propagation of action potentials. We still know very little, however, about how these functions...

This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A....

Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C...

Protection of neurons, as well as maintenance of their general homeostasis and trophic support is performed by glial cells. Astrocytes, the most abundant glial cell, increase in size and number evolutionarily such that invertebrates contain fewer small astrocytes, while humans have large multi-branched astrocytes that constitute up to 60% of centra...