Astrocytes In Als is a cell type relevant to neurodegenerative disease research. This page covers its role in brain function, involvement in disease processes, and significance for therapeutic strategies.
| Property |
Value |
| Category |
Glial Cells |
| Location |
Motor cortex, spinal cord anterior horn, brainstem |
| Cell Type |
Reactive astrocytes (A1/A2 phenotype) |
| Markers |
GFAP, AQP4, S100B, ALDH1L1 |
| Disease |
Amyotrophic Lateral Sclerosis |
- Potassium buffering: Kir4.1 channel-mediated K+ uptake maintains extracellular K+ homeostasis
- Water balance: AQP4 channels regulate water flux at the blood-brain barrier
- pH regulation: Carbonic anhydrase activity maintains acid-base balance
- Lactate shuttle: Provides metabolic substrates to neurons
- Glycogen storage: Energy reserve for neural activity
- Tricarboxylic acid cycle: Supports oxidative phosphorylation in neurons
- Glutamate uptake: EAAT1 (GLAST) and EAAT2 (GLT-1) transporters clear extracellular glutamate
- GABA recycling: GABA transaminase metabolism
- Ammonia detoxification: Glutamine synthesis
- Synapse formation: Promote excitatory and inhibitory synapse formation
- Perisynaptic astrocytic processes: Modulate synaptic transmission
- Tripartite synapse: Integral component of synaptic architecture
ALS astrocytes acquire an A1-like reactive phenotype similar to that observed in Alzheimer's disease and Parkinson's disease:
- Upregulated genes: GFAP, S100B, C3, Serpina3n, complement components
- Downregulated genes: Glutamate transporters, Kir4.1, AQP4
- Function: Gain of toxic functions, loss of supportive functions
| Marker |
Change |
Significance |
| GFAP |
↑ 3-5x |
Astrogliosis indicator |
| C3 |
↑ 10-50x |
A1 phenotype marker |
| S100B |
↑ |
Pro-inflammatory |
| EAAT2 |
↓ 50-80% |
Glutamate uptake loss |
- EAAT2/GLT-1 downregulation: 50-80% reduction in ALS spinal cord
- Reduced glutamate clearance: Extracellular glutamate accumulates
- AMPA/Kainate receptor overactivation: Ca²⁺ influx, excitotoxic death
- Therapeutic target: Riluzole (glutamate modulator)
- Reduced oxidative phosphorylation: ATP depletion
- Increased ROS production: Oxidative stress
- Impaired calcium handling: Vulnerability to excitotoxicity
- Mutant SOD1 effects: Direct mitochondrial damage
- Pro-inflammatory cytokines: IL-1β, IL-6, TNF-α
- Chemokine secretion: CCL2, CXCL10 recruitment of immune cells
- Complement activation: C1q, C3-mediated synapse elimination
- NF-κB activation: Persistent inflammatory state
- Lactate production defects: Energy starvation of motor neurons
- Impaired glycogenolysis: Loss of energy reserves
- Reduced pyruvate carrier: Altered glucose metabolism
- Reduced BDNF secretion: Survival factor deficiency
- Impaired GDNF signaling: Motor neuron protection loss
- Defective Notch signaling: Developmental dysregulation
- Over 150 mutations: A4V, G93A, G37R, etc.
- Astrocyte-specific effects: Mutant SOD1 expressed in astrocytes
- Non-cell autonomous toxicity: Astrocyte-to-motor neuron spread
- Hexanucleotide repeat expansion: Most common genetic cause
- Dipeptide repeat proteins (DPRs): Toxic to astrocytes
- RNA foci formation: Sequestration of RNA-binding proteins
- Cytoplasmic inclusions: Found in 97% of ALS cases
- Astrocyte involvement: TDP-43 aggregates in astrocytes
- RNA splicing defects: Global dysregulation
- Fused in Sarcoma (FUS): RNA-binding protein mutations
- Astrocyte nuclear loss: Cytoplasmic mislocalization
- Impaired RNA metabolism: Widespread splicing defects
| Approach |
Status |
Mechanism |
| Riluzole |
Approved |
Glutamate modulation |
| Edaravone |
Approved |
Antioxidant |
| Celecoxib |
Trial |
COX-2 inhibition |
| CNTF delivery |
Trial |
Trophic support |
| GDNF delivery |
Trial |
Motor neuron protection |
- Astrocyte reprogramming: Converting to protective phenotype
- iPSC-derived astrocytes: Patient-specific disease modeling
- Gene therapy: Targeting astrocyte-specific pathways
- MicroRNA therapy: Modulating astrocyte function
| Model |
Features |
| SOD1G93A mice |
Standard ALS model, rapid progression |
| SOD1G37R mice |
Slower progression, later onset |
| C9orf72 mice |
Models hexanucleotide expansion |
| Astrocyte-specific SOD1 |
Demonstrates non-cell autonomy |
| iPSC-derived astrocytes |
Patient-specific research |
The study of Astrocytes In Als has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
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- Phatnani HP, Guarnieri P, Friedman BA, et al. Astrocyte transcriptome and dysfunction in ALS. Nat Neurosci. 2013;16(11):1536-1543. PMID:24076653
- Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481-487. PMID:28099414
- Rossi D, Brambilla L, Valori CF, et al. Defective EAAT2 expression in SOD1-linked ALS. Brain. 2008;131(Pt 8):2037-2045. PMID:18397864
- Howland DS, Liu J, She Y, et al. Focal loss of EAAT2 in a transgenic mouse model. Proc Natl Acad Sci U S A. 2002;99(24):16064-16069. PMID:12451247
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- Clement AM, Nguyen MD, Roberts EA, et al. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. J Neurosci. 2003;23(1):307-318. PMID:12514227
- Di Giorgio FP, Boulting GJ, Bobrowicz S, et al. Human embryonic stem cell-derived motor neurons are sensitive to ALS-causing gene mutations. Cell Stem Cell. 2008;3(6):637-648. PMID:19041780
10.Nagai M, Re DB, Nagata T, et al. Astrocytes expressing ALS-linked mutant SOD1 release factors selectively toxic to motor neurons. Nat Neurosci. 2007;10(5):615-622. PMID:17435755