☆ 4.4 Review

Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders

NATURE REVIEWS NEUROSCIENCE (2023)

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Article Neurosciences

Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level

Erik C. B. Johnson et al.

Summary: This study analyzed the proteomes of over 1,000 brain tissues and identified new protein co-expression modules associated with Alzheimer's disease. These modules were highly conserved across cohorts and brain regions and revealed a proteopathic nature of the disease. The study also found disease-associated modules unique to the proteome, which could serve as potential therapeutic targets and biomarkers for Alzheimer's disease.

NATURE NEUROSCIENCE (2022)

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Review Biotechnology & Applied Microbiology

Function and therapeutic value of astrocytes in neurological diseases

Hong-Gyun Lee et al.

Summary: This review discusses astrocytes, a type of glial cell that is involved in various neurological diseases. Astrocytes regulate important processes in the central nervous system, such as glutamate and ion homeostasis, cholesterol and sphingolipid metabolism, and response to environmental factors. The review highlights the potential of targeting astrocytes for therapeutic intervention, including manipulating their metabolism and targeting transporters and receptors on astrocytes. The review also proposes a new nomenclature for astrocyte subsets to better understand their roles in neurological diseases.

NATURE REVIEWS DRUG DISCOVERY (2022)

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Review Neurosciences

Direct neuronal reprogramming: Fast forward from new concepts toward therapeutic approaches

Riccardo Bocchi et al.

Summary: A successful experiment conducted 20 years ago opened up the field of neuronal reprogramming, which has since made significant progress. These studies are not only important for clinical applications, but also provide fundamental insights into the mechanisms of cell conversion into neurons and the maintenance of neuronal identity.

NEURON (2022)

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Article Multidisciplinary Sciences

Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aβ pathology

Zoeb Jiwaji et al.

Summary: Alzheimer's disease affects astrocytes, and both A beta and Tau pathology induce changes in astrocytes. A beta mainly influences the expression of AD risk genes, while both pathologies induce age-dependent changes and have overlapping features with astrocytes found in post-mortem AD patients. Both A beta and Tau pathology alter the characteristics of astrocytes, including repression of bioenergetic and translation machinery, induction of inflammation pathways, and expression of protein degradation/proteostasis genes. Astrocyte-specific expression of Nrf2, a protective factor, can recapitulate elements of these astrocyte changes and reduce A beta deposition and phospho-tau accumulation. This Nrf2 expression also improves brain-wide transcriptional deregulation, cellular pathology, neurodegeneration, and behavioral/cognitive deficits.

NATURE COMMUNICATIONS (2022)

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Article Neurosciences

Induction of Parkinsonian-Like Changes via Targeted Downregulation of Astrocytic Glutamate Transporter GLT-1 in the Striatum

Chao Ren et al.

Summary: This study found that knocking down astrocytic GLT-1 could lead to PD-like changes, including impaired motor function, abnormal gait, and depression-like features. Additionally, the dopaminergic system was impaired and the count of tyrosine hydroxylase (TH) positive neurons was reduced in astrocytic GLT-1 knockdown rats. Blocking glutamate excitotoxicity may provide a new strategy for the prevention and treatment of PD.

JOURNAL OF PARKINSONS DISEASE (2022)

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Article Clinical Neurology

Astrocyte-neuron interplay is critical for Alzheimer's disease pathogenesis and is rescued by TRPA1 channel blockade

Adrien Paumier et al.

Summary: Understanding the sequence of cellular dysfunctions in preclinical Alzheimer's disease is crucial for developing new therapeutic strategies. The hyperactivity of hippocampal neurons is an early event in both humans and mouse models. This study shows that chronic inhibition of the TRPA1 channel can protect against Alzheimer's disease progression by normalizing astrocytic activity, preventing neuronal dysfunction, and preserving synaptic integrity.

BRAIN (2022)

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Article Clinical Neurology

Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson's disease

Ludovica Iovino et al.

Summary: This study demonstrates that the pathogenic variant G2019S of leucine-rich repeat kinase 2 (LRRK2) impairs the function of Excitatory Amino Acid Transporter 2 (EAAT2), resulting in glutamate overload in the brain, which may contribute to neurodegeneration in Parkinson's disease (PD).

ACTA NEUROPATHOLOGICA (2022)

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Review Biochemistry & Molecular Biology

Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: cause, consequence, or epiphenomenon?

Hannelore Hartmann et al.

Summary: ALS is a common adult-onset motor neuron disease characterized by selective degeneration of motor neurons. Dyslipidemia, particularly abnormal cholesterol levels, has been reported in ALS patients, but its specific role in the disease remains unclear. Further research is needed to understand the potential contribution of cholesterol metabolism to ALS.

FEBS JOURNAL (2022)

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Article Neurosciences

Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer's disease

Elena Galea et al.

Summary: The phenotypic transformation of astrocytes in Alzheimer's disease is still not well understood. This study reveals the molecular heterogeneity of individuals with the same clinical diagnosis and highlights the down-regulation of neuronal genes and up-regulation of astrocytic genes. These findings provide insights into the mechanism of astrocytic transformation in Alzheimer's disease.

NEUROBIOLOGY OF DISEASE (2022)

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Article Neurosciences

Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer's disease

Jessica S. Sadick et al.

Summary: This study used single-nuclei RNA sequencing to investigate the transcriptomic heterogeneity of astrocytes and oligodendrocytes in Alzheimer's disease (AD) patients. The findings revealed global and subtype-specific transcriptomic changes in these glial cells between AD and non-symptomatic brains, as well as the localization of heterogeneous astrocyte subtypes in specific brain regions using spatial transcriptomics resources.

NEURON (2022)

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Article Neurosciences

Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons

Cristian Arredondo et al.

Summary: Non-cell-autonomous mechanisms, specifically the release of unidentified toxic factors by astrocytes, contribute to the neurodegenerative diseases ALS and FTD. Studies found that astrocytes with ALS/FTD-related mutations display elevated levels of intracellular inorganic polyphosphate (polyP), which is also present in astrocyte-conditioned media (ACM). Degradation or neutralization of polyP in ALS/FTD astrocytes or ACM prevents the death of motoneurons. Additionally, polyP staining signals are enriched in postmortem ALS spinal cord sections and ALS cerebrospinal fluid (CSF) exhibits increased concentrations of polyP, suggesting polyP as a potential therapeutic target and biomarker for ALS/FTD.

NEURON (2022)

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Article Biochemistry & Molecular Biology

Cholesterol and matrisome pathways dysregulated in astrocytes and microglia

Julia Tcw et al.

Summary: The impact of APOE4 on human brain cellular function remains unclear. This study investigates the mechanisms by which APOE4 affects brain cells and reveals dysregulation of cholesterol metabolism and extracellular matrix in astrocytes, which may contribute to increased risk of AD.

CELL (2022)

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Article Biochemistry & Molecular Biology

Revisiting astrocyte to neuron conversion with lineage tracing in vivo

Lei-Lei Wang et al.

Summary: Recent studies have shown that in vivo cell fate conversions may not actually be converting astrocytes into neurons, but instead utilizing endogenous neurons. Lineage tracing strategies are necessary to accurately track the origin of converted cells, highlighting the importance of applying stringent tracing techniques in studies of cell fate conversions in vivo.

CELL (2021)

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Article Neurosciences

Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease

Nicholas S. Caron et al.

Summary: This study investigated the mechanisms of mHTT clearance from the brain in adult mice to elucidate the significance of therapy-induced CSF mHTT changes. The data supports both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons.

JOURNAL OF NEUROSCIENCE (2021)

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Article Neurosciences

α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss

Dorit Trudler et al.

Summary: In Parkinson's disease, synaptic and neuronal loss are prominent features. The study reveals that alpha Syn oligomers induce excessive glutamate release from astrocytes, activating NMDARs on neurons and leading to synaptic damage. However, the drug NitroSynapsin shows promise in protecting synapses from alpha Syn-induced damage.

JOURNAL OF NEUROSCIENCE (2021)

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Review Biochemical Research Methods

Deciphering molecular interactions by proximity labeling

Wei Qin et al.

Summary: This article introduces the proximity labeling technology for studying and applying molecular interactions. By fusing baits with promiscuous enzymes, endogenous molecules interacting with them can be tagged and identified by mass spectrometry or nucleic acid sequencing. PL technology has been used to map protein-protein, protein-RNA, and protein-DNA interactions.

NATURE METHODS (2021)

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Article Neurosciences

Molecular characterization of selectively vulnerable neurons in Alzheimer's disease

Kun Leng et al.

Summary: The study reveals the molecular signature of neuronal subpopulations vulnerable to tau aggregation and death in Alzheimer's disease, validating RORB as a marker. Using single-nucleus RNA sequencing, the research identified and characterized vulnerable neurons in the entorhinal cortex, as well as a subpopulation of astrocytes likely representing reactive astrocytes.

NATURE NEUROSCIENCE (2021)

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Article Multidisciplinary Sciences

Filamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex

Peng Wang et al.

Summary: Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The entry of filamentous recombinant human Tau into astrocytes via the integrin alpha V/beta 1 complex stimulates integrin signaling, resulting in activation of NF kappa B and astrocyte conversion towards a neurotoxic state.

NATURE COMMUNICATIONS (2021)

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Article Neurosciences

Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology

Kornelia Szebenyi et al.

Summary: This study presented a cerebral organoid slice model derived from human induced pluripotent stem cells that recapitulates mature cortical architecture and displays early molecular pathology of ALS/FTD. Distinct transcriptional, proteostasis, and DNA repair disturbances in astroglia and neurons were revealed using single-cell RNA sequencing and biological assays. The results suggest that patient-specific iPSC-derived cortical organoid slice cultures can provide insights into preclinical ALS/FTD mechanisms and potential therapeutic approaches.

NATURE NEUROSCIENCE (2021)

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Article Neurosciences

Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance

Linn Streubel-Gallasch et al.

Summary: This study compared the ability of astrocytes carrying PD-linked gene mutations with normal astrocytes in handling α-synuclein, finding a decreased clearance capacity in mutant cells linked to a loss of function in AnxA2.

MOLECULAR NEUROBIOLOGY (2021)

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Article Neurosciences

Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer's disease neuropathology

Fading Chen et al.

Summary: In this study, researchers found that astrocyte-secreted Clusterin co-localizes with presynaptic puncta of excitatory neurons in the central nervous system. Loss of Clusterin led to impaired presynaptic function and reduced spine density in vivo. Enhancing astrocytic Clusterin expression promoted excitatory neurotransmission and rescued synaptic deficits, offering potential therapeutic strategies for late-onset Alzheimer's disease.

MOLECULAR NEURODEGENERATION (2021)

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Review Neurosciences

Reactive astrocyte nomenclature, definitions, and future directions

Carole Escartin et al.

Summary: The article highlights the challenges and uncertainties surrounding reactive astrocytes, advocating for comprehensive research that includes assessment of multiple molecular and functional parameters, preferably in vivo, along with multivariate statistics and determination of impact on pathological hallmarks in relevant models.

NATURE NEUROSCIENCE (2021)

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Article Neurosciences

Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

Kristen R. Maynard et al.

Summary: This study defined spatial gene expression in the human dorsolateral prefrontal cortex, revealing layer-enriched expression of genes associated with schizophrenia and autism, highlighting the clinical relevance of spatially defined expression.

NATURE NEUROSCIENCE (2021)

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Article Cell Biology

Antisense therapy in a rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment

Tracy L. Hagemann et al.

Summary: This study introduces a novel rat model of Alexander disease exhibiting hallmark pathology, and demonstrates the potential of ASO therapy to prevent and reverse various aspects of the disease.

SCIENCE TRANSLATIONAL MEDICINE (2021)

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Article Biology

The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease

Aurelie de Rus Jacquet et al.

Summary: This study focused on the effects of a Parkinson's disease-related mutation on astrocytes and neurons, revealing alterations in extracellular vesicle biogenesis and abnormal accumulation of PD-related proteins. The findings suggest that dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of Parkinson's disease.

ELIFE (2021)

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Article Clinical Neurology

SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes

Giulia Birolini et al.

Summary: This study highlights the importance of glial SREBP2 in the pathogenesis of Huntington's disease and demonstrates that AAV-based delivery of SREBP2 to astrocytes can counteract key features of the disease.

BRAIN (2021)

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Article Clinical Neurology

Subclinical epileptiform activity accelerates the progression of Alzheimer's disease: A long-term EEG study

Andras Attila Horvath et al.

Summary: Subclinical epileptiform activity is more common in Alzheimer's disease patients than in healthy elderly individuals, and is associated with lower memory performance. Alzheimer's patients with epileptiform discharges show a faster decline in global cognitive scores, with a strong correlation between cognitive decline and spike frequency.

CLINICAL NEUROPHYSIOLOGY (2021)

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Article Cell Biology

Reactive astrocytes facilitate vascular repair and remodeling after stroke

Michael R. Williamson et al.

Summary: This study demonstrates that reactive astrocytes play a crucial role in vascular repair and remodeling after ischemic stroke in mice, by activating transcriptional programs related to vascular remodeling. Ablation of reactive astrocytes significantly impairs vascular and extracellular matrix remodeling, leading to prolonged blood flow deficits, exacerbated vascular permeability, ongoing cell death, and worsened motor recovery. These findings highlight the critical role of reactive astrocytes as cellular mediators of vascular remodeling during neural repair.

CELL REPORTS (2021)

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Article Biology

Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis

Tarik Seref Onur et al.

Summary: Research shows that glia cells play a crucial role in the formation and maintenance of synapses in neurodegenerative diseases. Lowering genes involved in synapse assembly can alleviate pathological and behavioral deficits. Conserved gene dysregulation is observed in patients with neurodegenerative diseases, fruit flies, and mice.

ELIFE (2021)

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Neuroinflammatory astrocyte subtypes in the mouse brain

Philip Hasel et al.

Summary: This study investigated the transcriptome changes of mouse cortical astrocytes after an acute inflammatory stimulus, revealing rapid and drastic changes over time. By sequencing thousands of astrocytes at single-cell resolution, it was shown that inflammation causes a widespread response with distinct subtypes undergoing inflammatory transitions with defined transcriptomic profiles. Spatial transcriptomics and in situ hybridization were used to attribute specific inflammation-induced reactive astrocyte sub-states to certain brain regions.

NATURE NEUROSCIENCE (2021)

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Treatments for Alzheimer's disease emerge

Dennis J. Selkoe

SCIENCE (2021)

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Generation of a Novel Mouse Model of Parkinson's Disease via Targeted Knockdown of Glutamate Transporter GLT-1 in the Substantia Nigra

Yunlong Zhang et al.

ACS CHEMICAL NEUROSCIENCE (2020)

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Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology

Chen Zhao et al.

GLIA (2020)

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Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease

Oceane Guillemaud et al.

NEUROBIOLOGY OF AGING (2020)

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APOE alters glucose flux through central carbon pathways in astrocytes

Holden C. Williams et al.

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Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression

Bing Bai et al.

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Single-nucleus RNA-seq identifies Huntington disease astrocyte states

Osama Al-Dalahmah et al.

ACTA NEUROPATHOLOGICA COMMUNICATIONS (2020)

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Glia-to-Neuron Conversion by CRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice

Haibo Zhou et al.

CELL (2020)

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Bor Luen Tang

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The blood-brain barrier in health and disease: Important unanswered questions

Caterina P. Profaci et al.

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Astroglia and Tau: New Perspectives

Gabor G. Kovacs

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Recessively-Inherited Adult-Onset Alexander Disease Caused by a Homozygous Mutation in the GFAP Gene

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Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation

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Region-Specific Transcriptional Control of Astrocyte Function Oversees Local Circuit Activities

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BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology

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Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice

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Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model

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Identification of Conserved Proteomic Networks in Neurodegenerative Dementia

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Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

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Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer's disease

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Metabolic alterations in Parkinson's disease astrocytes

Tuuli-Maria Sonninen et al.

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APOE2 is associated with longevity independent of Alzheimer's disease

Mitsuru Shinohara et al.

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Neuron-Astrocyte Interactions in Parkinson's Disease

Ikuko Miyazaki et al.

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The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics

Edward Pajarillo et al.

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Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration

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Silas Maniatis et al.

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Extracellular Monomeric Tau Is Internalized by Astrocytes

Juan Ramon Perea et al.

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A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation

Alexandra Grubman et al.

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Astrocyte molecular signatures in Huntington's disease

Blanca Diaz-Castro et al.

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Quantitative proteomics reveals distinct composition of amyloid plaques in Alzheimer's disease

Feng Xiong et al.

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A Novel Mutation of GFAP Causing Adult-Onset Alexander Disease

Andrea Ciammola et al.

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Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

Nicole Reichenbach et al.

EMBO MOLECULAR MEDICINE (2019)

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Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk

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Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity

Anastasya Birger et al.

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Astrocytes expressing ALS-linked mutant FUS induce motor neuron death through release of tumor necrosis factor-alpha

Azadeh Kia et al.

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P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer's disease model

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Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength

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APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types

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Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation

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Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer's Disease

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Astrocyte-Secreted Chordin-like 1 Drives Synapse Maturation and Limits Plasticity by Increasing Synaptic GluA2 AMPA Receptors

Elena Blanco-Suarez et al.

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Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer's disease

Kelly Ceyzeriat et al.

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APOE ε4/ε4 diminishes neurotrophic function of human iPSC-derived astrocytes

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TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide

Anthony Bosson et al.

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ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

Yang Shi et al.

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Neurotoxic reactive astrocytes are induced by activated microglia

Shane A. Liddelow et al.

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