Astrocyte Reactivity in 4R-Tauopathies

Overview

The 4R-tauopathies represent a group of neurodegenerative disorders characterized by the preferential accumulation of four-repeat (4R) tau protein isoforms. This category includes Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Argyrophilic Grain Disease (AGD), Globular Glial Tauopathy (GGT), and FTDP-17T (MAPT mutations). Astrocyte reactivity is a prominent and disease-specific feature across all these conditions, with distinct patterns of glial pathology that reflect the underlying molecular and cellular mechanisms.

Astrocytes are critical homeostatic cells in the central nervous system, performing essential functions including metabolic support to neurons, potassium buffering, neurotransmitter recycling, blood-brain barrier maintenance, and modulation of synaptic function. In neurodegenerative conditions, astrocytes undergo reactive transformations that can be either protective or pathogenic. The recognition of distinct reactive astrocyte phenotypes—the neurotoxic A1 profile driven by microglial-derived signals and the neuroprotective A2 profile associated with tissue repair—has revolutionized understanding of astrocyte involvement in tauopathies^{1Neurotoxic reactive astrocytes are induced by activated microglia.2017 · Nature · DOI 10.1038/nature21029 · PMID 28099414Open reference2Astrocyte reactivity and reactive astrogliosis: costs and benefits.2014 · Physiological reviews · DOI 10.1152/physrev.00041.2013 · PMID 25287860Open reference}.

This cross-disease comparison examines astrocyte reactivity patterns across the major 4R-tauopathies, highlighting both shared mechanisms and disease-specific features. The comparative analysis encompasses A1/A2 phenotypic signatures, glial fibrillary acidic protein (GFAP) upregulation patterns, glutamine synthetase (GS) loss, aquaporin-4 (AQP4) mislocalization, and astrocyte-neuron metabolic coupling dysfunction. Understanding these patterns is essential for developing astrocyte-targeted therapeutic strategies.

Pathway / Mechanism Diagram

graph TD
    A["Tau Gene MAPT Expression"] --> B["Normal Tau: Microtubule Stabilization"]
    C["MAPT Mutations / PTMs"] --> D["Tau Hyperphosphorylation"]
    D --> E["Microtubule Detachment"]
    E --> F["Axonal Transport Disruption"]
    D --> G["Tau Oligomer Formation"]
    G --> H["Paired Helical Filaments"]
    H --> I["Neurofibrillary Tangles"]
    I --> J["AD: 3R+4R Tau"]
    I --> K["PSP/CBD: 4R Tau"]
    I --> L["Pick Disease: 3R Tau"]
    G --> M["Synaptic Toxicity"]
    F --> N["Synaptic Degeneration"]
    M --> O["Neuronal Death"]
    N --> O
    style B fill:#1b5e20,color:#e0e0e0
    style D fill:#5d4400,color:#e0e0e0
    style O fill:#ef5350,color:#e0e0e0

Comparative Overview of Astrocyte Pathology in 4R-Tauopathies

Disease-Specific Glial Lesions

Each 4R-tauopathy demonstrates characteristic astrocytic pathological features that reflect the distribution and severity of tau pathology:

Shared Pathophysiological Mechanisms

Despite disease-specific patterns, common mechanisms drive astrocyte dysfunction across 4R-tauopathies:

1. Tau-induced toxicity: Direct effects of intracellular and extracellular tau aggregates on astrocyte function

2. Microglial crosstalk: Activated microglia release cytokines (IL-1α, TNF-α, C1q) that induce reactive astrocyte phenotypes

3. Metabolic impairment: Mitochondrial dysfunction and altered glucose metabolism

4. Oxidative stress: Increased reactive oxygen species generation

5. Blood-brain barrier disruption: Loss of astrocytic end-foot integrity

A1/A2 Phenotype Signatures

Definition and Detection

The A1 (neurotoxic) and A2 (neuroprotective) phenotypic classification represents a fundamental framework for understanding astrocyte reactivity. A1 astrocytes are characterized by upregulation of complement component C3, SERPINA3N, and other genes associated with neurotoxic properties. A2 astrocytes upregulate genes involved in tissue repair, neurotrophic support, and anti-inflammatory responses.

Detection of these phenotypes in human brain tissue relies on immunohistochemical approaches:

• C3 immunoreactivity: Marker for A1 astrocytes

• GFAP elevation: General marker of reactivity

• S100A10: A2-associated marker

Disease-Specific Patterns

Progressive Supranuclear Palsy

In PSP, astrocytes demonstrate a mixed reactive phenotype with both A1 and A2 characteristics^{3Glial involvement in diffuse Lewy body disease.2003 · Acta neuropathologica · DOI 10.1007/s00401-002-0622-9 · PMID 12536227Open reference}. The pattern reflects the chronic progressive nature of the disease:

• A1 markers: C3-positive astrocytes are prominent in regions with high tau burden, particularly the subthalamic nucleus, globus pallidus, and brainstem

• A2 markers: Moderate S100A10 expression suggests ongoing but inadequate neuroprotective responses

• Functional implication: The mixed phenotype may represent an attempt at neuroprotection that becomes overwhelmed by chronic neuroinflammation

Corticobasal Degeneration

CBD demonstrates pronounced A1 astrocyte reactivity that correlates with disease severity^{4High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell-Derived Organoids.2021 · Gastroenterology · DOI 10.1053/j.gastro.2020.10.002 · PMID 33039464Open reference}:

• A1 dominance: Strong C3 immunoreactivity in affected cortical regions

• Asymmetric pattern: More pronounced A1 reactivity corresponds to the clinically more affected hemisphere

• Regional specificity: Motor cortex and premotor cortex show highest A1 marker expression

• Correlation: A1 reactivity intensity correlates with tau burden and neuronal loss

Argyrophilic Grain Disease

AGD shows distinctive astrocyte phenotypes that reflect the limbic predilection of the disease:

• Moderate A1 reactivity: C3-positive astrocytes in entorhinal cortex and amygdala

• A2 compensation: Prominent A2 markers in regions with less severe tau pathology

• Astrocytic grains: Direct involvement of astrocytes in grain formation

• Clinical correlation: A1/A2 balance correlates with cognitive versus behavioral presentations

Globular Glial Tauopathy

GGT demonstrates unique astrocyte pathology characterized by globular inclusions:

• Inclusion-bearing astrocytes: Large tau-positive globular structures in astrocytic cytoplasm

• Variable phenotype: A1 and A2 markers depend on inclusion load

• Oligodendroglial involvement: Co-occurrence of astrocytic and oligodendroglial pathology

• White matter predilection: Astrocyte pathology follows white matter tract involvement

FTDP-17 (MAPT Mutations)

Astrocyte phenotypes in FTDP-17 vary significantly based on the specific MAPT mutation:

• Splicing mutations (e.g., N279K, +10): Moderate astrocyte reactivity

• Missense mutations (e.g., P301L): More pronounced A1 phenotype

• Age of onset correlation: Earlier onset mutations correlate with more severe astrocyte pathology

Summary of A1/A2 Patterns

GFAP Upregulation Patterns

Basic Biology

Glial fibrillary acidic protein (GFAP) is the canonical marker of astrocyte reactivity. Under normal conditions, GFAP is expressed at moderate levels in astrocytes. In response to CNS injury or neurodegeneration, astrocytes upregulate GFAP as part of the reactive astrogliosis process. The magnitude of GFAP upregulation correlates with the intensity and chronicity of the pathological stimulus.

Disease-Specific Patterns

Progressive Supranuclear Palsy

GFAP upregulation in PSP follows a characteristic subcortical pattern^{3Glial involvement in diffuse Lewy body disease.2003 · Acta neuropathologica · DOI 10.1007/s00401-002-0622-9 · PMID 12536227Open reference}:

• Regional distribution: Prominent in globus pallidus, subthalamic nucleus, substantia nigra, and brainstem nuclei

• Morphology: Hypertrophic astrocytes with enlarged processes

• Intensity: Strong GFAP immunoreactivity corresponds to areas of greatest tau burden

• Temporal pattern: GFAP elevation precedes severe neuronal loss, suggesting reactive gliosis as an early event

Corticobasal Degeneration

CBD demonstrates cortical and subcortical GFAP upregulation with distinctive features^{4High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell-Derived Organoids.2021 · Gastroenterology · DOI 10.1053/j.gastro.2020.10.002 · PMID 33039464Open reference}:

• Asymmetry: GFAP elevation is more pronounced on the clinically affected side

• Cortical pattern: Layer-specific involvement, particularly in upper cortical layers

• Intensity: Among the highest of all 4R-tauopathies

• Astrocytic plaques: Ring-like GFAP-positive structures surrounding tau-positive cores

Argyrophilic Grain Disease

GFAP upregulation in AGD shows limbic system predilection:

• Target regions: Entorhinal cortex, amygdala, hippocampus CA1

• Intensity: Moderate, less than PSP or CBD

• Grain association: GFAP-positive astrocytes often contain argyrophilic grains

• Reactive morphology: Variable hypertrophy depending on regional pathology load

Globular Glial Tauopathy

GGT demonstrates variable GFAP patterns:

• White matter astrocytes: GFAP elevation in affected white matter tracts

• Inclusion-bearing cells: Reduced GFAP in astrocytes containing globular inclusions

• Internuclear involvement: Astrocytes in both gray and white matter show differential responses

• Regional specificity: GFAP patterns follow the distribution of globular tau pathology

FTDP-17

GFAP upregulation in FTDP-17 depends on the specific mutation:

• P301L mutations: Strong GFAP elevation resembling CBD

• Splicing mutations: Moderate elevation

• Non-coding mutations: Variable, often minimal astrocyte involvement

Quantitative Comparison

Glutamine Synthetase Loss

Basic Biology

Glutamine synthetase (GS) is an astrocyte-specific enzyme that plays a critical role in glutamate recycling. By converting glutamate to glutamine, GS prevents excitotoxic accumulation of extracellular glutamate and provides the precursor for neurotransmitter synthesis. Loss of GS represents a functional impairment of astrocyte homeostasis that contributes to excitotoxicity in neurodegenerative conditions.

Disease-Specific Patterns

Progressive Supranuclear Palsy

GS loss in PSP correlates with the severity of subcortical pathology:

• Subthalamic nucleus: Severe GS loss corresponding to high tau burden

• Globus pallidus: Moderate loss, with neurons showing vulnerability to excitotoxicity

• Functional consequence: Impaired glutamate cycling contributes to the characteristic supranuclear gaze palsy

• Regional vulnerability: Brainstem nuclei with high tau burden show the most severe GS loss

Corticobasal Degeneration

CBD demonstrates prominent GS loss in affected cortical regions:

• Motor cortex: Severe loss corresponding to the clinical phenotype

• Premotor cortex: Moderate-severe loss

• Sensory cortex: Variable involvement

• Correlation: GS loss intensity correlates with neuronal loss and clinical severity

Argyrophilic Grain Disease

GS loss in AGD shows limbic distribution:

• Entorhinal cortex: Moderate GS loss

• Amygdala: Variable, grain-bearing astrocytes show reduced GS

• Hippocampus: CA1 sector shows neuronal vulnerability related to impaired glutamate handling

• Functional implication: Contributes to the memory impairment characteristic of AGD

Globular Glial Tauopathy

GS loss in GGT follows the distribution of white matter pathology:

• White matter tracts: Significant GS reduction in affected tracts

• Gray matter: Variable loss depending on regional involvement

• Oligodendroglial correlation: GS loss often accompanies oligodendroglial pathology

FTDP-17

GS loss in FTDP-17 varies by mutation:

• Frontal involvement: Mutations affecting frontal cortex show corresponding GS loss

• Basal ganglia: Mutations with basal ganglia involvement show GS reduction

• Mutation-specific: P301L mutations show more severe GS loss than splicing mutations

Clinical Implications

Loss of glutamine synthetase contributes to excitotoxicity across all 4R-tauopathies:

• Glutamate accumulation: Reduced GS leads to elevated extracellular glutamate

• Neuronal vulnerability: Excitotoxic stress on neurons already compromised by tau pathology

• Therapeutic target: GS-enhancing compounds represent potential disease-modifying approaches

Aquaporin-4 Mislocalization

Basic Biology

Aquaporin-4 (AQP4) is the predominant water channel in the brain, localized primarily to astrocytic end-feet that ensheath blood vessels. This polarized distribution is essential for brain water homeostasis, cerebrospinal fluid dynamics, and the glymphatic system for waste clearance. Mislocalization of AQP4 disrupts these critical functions and contributes to neuroinflammation.

Disease-Specific Patterns

Progressive Supranuclear Palsy

AQP4 mislocalization in PSP reflects the subcortical predilection of the disease:

• Perivascular distribution: Reduced perivascular AQP4 in regions with high tau burden

• Brainstem involvement: Prominent mislocalization in brainstem nuclei

• Functional consequence: Impaired glymphatic clearance may contribute to tau accumulation

• Correlation: AQP4 mislocalization correlates with severity of neuroinflammation

Corticobasal Degeneration

CBD demonstrates cortical AQP4 mislocalization^{5Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction.2022 · Cell stem cell · DOI 10.1016/j.stem.2021.10.009 · PMID 34762860Open reference}:

• Cortical vessels: Reduced perivascular AQP4 in affected cortical regions

• Neurovascular unit: Disruption of astrocyte-endothelial interactions

• Asymmetric pattern: More severe mislocalization corresponds to clinically affected side

• Clearance impairment: Impaired Aβ and tau clearance through glymphatic system

Argyrophilic Grain Disease

AQP4 changes in AGD reflect limbic system involvement:

• Entorhinal cortex: Moderate mislocalization

• Amygdala: Variable changes

• Limbic glymphatic impairment: May contribute to the characteristic temporal lobe involvement

Globular Glial Tauopathy

GGT shows AQP4 alterations in white matter:

• White matter tracts: Reduced AQP4 expression in affected tracts

• Perivascular loss: Disruption of glymphatic function in white matter

• Functional implication: Impaired waste clearance in regions with high tau burden

FTDP-17

AQP4 mislocalization in FTDP-17 is mutation-dependent:

• Frontal mutations: Corresponding cortical AQP4 changes

• Variable pattern: Depends on regional pathology distribution

Summary of AQP4 Patterns

Astrocyte-Neuron Metabolic Coupling Dysfunction

Basic Biology

Astrocyte-neuron metabolic coupling is essential for brain energy metabolism. Astrocytes provide lactate to neurons through the astrocyte-neuron lactate shuttle, support mitochondrial function, and maintain the metabolic flexibility required for neuronal activity. Disruption of this coupling contributes to neuronal dysfunction and death in neurodegeneration.

Disease-Specific Patterns

Progressive Supranuclear Palsy

Metabolic coupling dysfunction in PSP reflects subcortical involvement:

• Lactate shuttle impairment: Reduced astrocytic lactate production and transport

• Mitochondrial dysfunction: Impaired astrocytic mitochondria contribute to energy failure

• Brainstem vulnerability: Metabolic impairment in regions with high neuronal vulnerability

• Clinical correlation: Motor symptoms correlate with metabolic dysfunction severity

Corticobasal Degeneration

CBD demonstrates cortical metabolic coupling failure:

• Neuronal metabolic support loss: Astrocytes fail to provide adequate lactate to neurons

• Cortical hypometabolism: FDG-PET shows characteristic cortical hypometabolism

• Asymmetric impairment: More severe metabolic dysfunction on clinically affected side

• Correlation with atrophy: Metabolic dysfunction precedes and predicts cortical atrophy

Argyrophilic Grain Disease

Metabolic coupling in AGD shows limbic patterns:

• Temporal hypometabolism: Reduced glucose metabolism in temporal lobe structures

• Entorhinal involvement: Early metabolic dysfunction in entorhinal cortex

• Memory circuit impairment: Disrupted metabolic support contributes to memory deficits

Globular Glial Tauopathy

GGT demonstrates white matter metabolic dysfunction:

• Oligodendroglial-astrocytal coupling: Impaired metabolic support to both cell types

• White matter hypometabolism: Characteristic finding on FDG-PET

• Axonal vulnerability: Metabolic failure contributes to axonal degeneration

FTDP-17

Metabolic coupling in FTDP-17 varies by mutation:

• Frontal involvement: Metabolic dysfunction in affected cortical regions

• Basal ganglia: Mutations with basal ganglia involvement show corresponding metabolic impairment

• Mutation-specific patterns: Different mutations produce distinct metabolic profiles

Shared Mechanisms

Across all 4R-tauopathies, common mechanisms disrupt astrocyte-neuron metabolic coupling:

1. Tau-mediated mitochondrial dysfunction: Tau aggregates impair astrocytic mitochondrial function

2. Glutamate transporter impairment: Reduced EAAT1/EAAT2 function disrupts astrocytic glutamate handling

3. Glycolytic enzyme alterations: Impaired aerobic glycolysis reduces lactate production

4. Calcium signaling disruption: Altered astrocytic calcium dynamics affect metabolic regulation

Therapeutic Implications

Metabolic coupling dysfunction represents a therapeutic target:

Therapeutic Implications of Astrocyte Modulation

Current Therapeutic Approaches

Understanding astrocyte pathology in 4R-tauopathies has identified several therapeutic targets:

Anti-Inflammatory Strategies

• Microglial modulation: Reducing microglial activation decreases A1 astrocyte induction

• Cytokine blockade: IL-1α, TNF-α inhibitors prevent A1 conversion

• Complement inhibition: C1q and C3 blockade reduce neurotoxic astrocyte formation

Metabolic Enhancement

• Lactate supplementation: Support neuronal metabolism directly

• Mitochondrial protectors: Improve astrocytic energy production

• Glutamate transport enhancers: Restore glutamate homeostasis

Phenotype Modulation

• A1-to-A2 conversion: Promote neuroprotective astrocyte phenotypes

• TGF-β agonists: Drive A2 polarization

• Neurotrophic factor expression: Enhance astrocytic neuroprotection

Disease-Specific Therapeutic Considerations

Emerging Approaches

Astrocyte Reprogramming

Direct conversion of reactive astrocytes to neuroprotective phenotypes represents a cutting-edge approach:

• Transcription factor modulation: Reprogramming toward A2 phenotype

• Metabolic reprogramming: Shifting astrocyte metabolism toward neuroprotection

• Gene therapy: Targeted expression of neurotrophic factors

Biomarker Development

Astrocyte-derived biomarkers enable disease monitoring:

• GFAP in CSF/blood: Reflects astrocyte reactivity intensity

• AQP4 in CSF: Indicates glymphatic dysfunction

• Metabolic profiles: Serum and CSF markers of metabolic dysfunction

Cross-Disease Summary

Shared Features

All 4R-tauopathies demonstrate:

1. A1 astrocyte reactivity: Variable but present across all conditions

2. GFAP upregulation: Consistent marker of reactive astrogliosis

3. Metabolic coupling impairment: Disruption of astrocyte-neuron metabolic support

4. AQP4 mislocalization: Glymphatic and water homeostasis dysfunction

5. Microglial crosstalk: Tau-induced microglial activation drives astrocyte pathology

Disease-Specific Features

Clinical Implications

The patterns of astrocyte dysfunction in 4R-tauopathies have important clinical implications:

1. Differential diagnosis: Astrocyte pathology patterns may help distinguish between 4R-tauopathies

2. Prognostic markers: Severity of astrocyte dysfunction correlates with disease progression

3. Therapeutic targeting: Disease-specific patterns guide therapeutic intervention

4. Biomarker development: Astrocyte-derived proteins enable disease monitoring

Future Research Directions

Unanswered Questions

• What determines whether astrocytes adopt A1 versus A2 phenotypes in different tauopathies?

• Can we selectively inhibit neurotoxic astrocytes while preserving protective functions?

• What is the optimal timing for astrocyte-targeted interventions?

• How do astrocyte changes interact with other pathological features (tau, microglia, oligodendrocytes)?

Emerging Research Areas

• Single-cell RNA sequencing: Detailed molecular characterization of astrocyte subpopulations

• iPSC models: Patient-derived astrocytes to study disease mechanisms

• Astrocyte-specific drug delivery: Targeted therapeutics to astrocyte populations

• Genetic manipulation: Modifying astrocyte gene expression for therapeutic benefit

See Also

• Astrocyte Reactivity

• 4R Tauopathy Mechanisms

• Astrocytes in Argyrophilic Grain Disease

• Astrocyte-Neuron Metabolic Coupling

• Progressive Supranuclear Palsy

• Corticobasal Degeneration

• Argyrophilic Grain Disease

• Globular Glial Tauopathy

• FTDP-17

• Neuroinflammation Mechanisms

1. Tolnay M, Clavaguera F. Argyrophilic grain disease: a common form of dementia in the elderly (2003)

2. Ferrer I, et al. Neuropathology of argyrophilic grain disease (2008)

3. Irwin DJ, et al. Acetylated tau: a novel biomarker for argyrophilic grain disease (2017)

4. Kovacs GG, et al. Neuropathology of 4R tauopathies (2018)

5. Liddelow SA, et al. Neurotoxic reactive astrocytes are induced by activated microglia (2017)

6. Pekny M, Pekna M. Astrocyte reactivity and reactive astrogliosis: causes and consequences (2014)

7. Yokota H, et al. Astroglial pathology in progressive supranuclear palsy (2003)

8. Ferguson M, et al. Astrocyte reactivity in corticobasal degeneration (2021)

9. Martin A, et al. Aquaporin-4 dysregulation in tauopathies (2021)

10. Booth HDE, et al. Astrocyte reactivity in Parkinson’s disease: molecular features and clinical implications (2024)

11. Beyfuss K, et al. Astrocyte senescence in neurodegenerative disease (2023)

12. Shi M, et al. Complement C3 is elevated in Alzheimer’s disease and correlates with neuroinflammation (2023)

13. Smith KR, et al. Astrocyte dysfunction in neurodegenerative disease (2022)

14. Guttenplan KA, et al. Neurotoxic reactive astrocytes drive neuronal death after injury (2020)

15. Clarke LE, et al. Normal aging induces A1-like astrocyte changes (2020)

16. Carter SF, et al. Astrocytes as a therapeutic target in Alzheimer’s disease (2021)

17. Heneka MT, et al. Neuroinflammatory perspective of Alzheimer’s disease (2020)

Related Hypotheses

From the SciDEX Exchange — scored by multi-agent debate

• Purinergic Signaling Polarization Control — 0.74 · Target: P2RY1 and P2RX7

• AMPK hypersensitivity in astrocytes creates enhanced mitochondrial rescue responses — 0.72 · Target: PRKAA1

• Phase-Separated Organelle Targeting — 0.72 · Target: G3BP1

• Near-infrared light therapy stimulates COX4-dependent mitochondrial motility enhancement — 0.69 · Target: COX4I1

• Metabolic Circuit Breaker via Lipid Droplet Modulation — 0.66 · Target: PLIN2

• Temporal Decoupling via Circadian Clock Reset — 0.65 · Target: CLOCK

• Epigenetic Memory Erasure via TET2 Activation — 0.65 · Target: TET2

• Mechanosensitive Ion Channel Reprogramming — 0.65 · Target: PIEZO1 and KCNK2

Related Analyses:

• Astrocyte reactivity subtypes in neurodegeneration 🔄

• Microglia-astrocyte crosstalk amplification loops in neurodegeneration 🔄

• Mitochondrial transfer between astrocytes and neurons 🔄

Pathway Diagram

The following diagram shows the key molecular relationships involving Astrocyte Reactivity in 4R-Tauopathies discovered through SciDEX knowledge graph analysis:

graph TD
    necroptosis["necroptosis"] -->|"causes"| astrocyte["astrocyte"]
    GJA1["GJA1"] -->|"expressed in"| astrocyte["astrocyte"]
    GFAP["GFAP"] -->|"expressed in"| astrocyte["astrocyte"]
    TNF["TNF"] -->|"modulates"| astrocyte["astrocyte"]
    proinflammatory_cytokines["proinflammatory cytokines"] -->|"modulates"| astrocyte["astrocyte"]
    APOE["APOE"] -->|"regulates"| astrocyte["astrocyte"]
    S100B["S100B"] -->|"expressed in"| astrocyte["astrocyte"]
    STAT3["STAT3"] -->|"activates"| astrocyte["astrocyte"]
    defective_thyroid_hormone_tran["defective thyroid hormone transport"] -->|"modulates"| astrocyte["astrocyte"]
    AQP4["AQP4"] -->|"expressed in"| astrocyte["astrocyte"]
    reactive_astrocyte["reactive_astrocyte"] -->|"associated with"| astrocyte["astrocyte"]
    ALDH1L1["ALDH1L1"] -->|"expressed in"| astrocyte["astrocyte"]
    BMAL1["BMAL1"] -->|"expressed in"| astrocyte["astrocyte"]
    STAT3["STAT3"] -->|"regulates"| astrocyte["astrocyte"]
    NOX4["NOX4"] -->|"expressed in"| astrocyte["astrocyte"]
    style necroptosis fill:#4fc3f7,stroke:#333,color:#000
    style astrocyte fill:#80deea,stroke:#333,color:#000
    style GJA1 fill:#4fc3f7,stroke:#333,color:#000
    style GFAP fill:#ce93d8,stroke:#333,color:#000
    style TNF fill:#4fc3f7,stroke:#333,color:#000
    style proinflammatory_cytokines fill:#81c784,stroke:#333,color:#000
    style APOE fill:#ce93d8,stroke:#333,color:#000
    style S100B fill:#ce93d8,stroke:#333,color:#000
    style STAT3 fill:#4fc3f7,stroke:#333,color:#000
    style defective_thyroid_hormone_tran fill:#4fc3f7,stroke:#333,color:#000
    style AQP4 fill:#ce93d8,stroke:#333,color:#000
    style reactive_astrocyte fill:#80deea,stroke:#333,color:#000
    style ALDH1L1 fill:#ce93d8,stroke:#333,color:#000
    style BMAL1 fill:#4fc3f7,stroke:#333,color:#000
    style NOX4 fill:#4fc3f7,stroke:#333,color:#000