Glial cells (neuroglia) are non-neuronal cells that constitute approximately 50% of the human brain volume. Once considered mere support cells, astrocytes, oligodendrocytes, and microglia are now recognized as active participants in neural circuit function, synaptic transmission, and brain homeostasis .
The most abundant glial cell type in the CNS, astrocytes outnumber neurons by approximately 5:1 in human cortex.
Characteristics:
- Star-shaped cells with multiple branching processes
- Express GFAP (glial fibrillary acidic protein)
- Contact both blood vessels and neurons
- Form the blood-brain barrier alongside endothelial cells
Functions:
- Synaptic support: Provide metabolic support to neurons, recycle neurotransmitters
- Ion homeostasis: Regulate extracellular potassium and calcium
- Water balance: Aquaporin-4 channels for water transport
- Neuroinflammation: Release cytokines and chemokines in response to injury
¶ Oligodendrocytes (CNS) and Schwann Cells (PNS)
Responsible for myelinating axons in the CNS and PNS respectively.
CNS Oligodendrocytes:
- Each oligodendrocyte myelinates multiple axons (up to 50)
- Express MBP (myelin basic protein) and PLP (proteolipid protein)
- Form internodes with nodes of Ranvier for saltatory conduction
PNS Schwann Cells:
- Myelinate single axons
- Express P0 and PMP22 proteins
- Support peripheral nerve regeneration
The resident immune cells of the brain, derived from yolk sac progenitors.
Characteristics:
- Small cell bodies with ramified processes
- Express IBA1 (ionized calcium-binding adapter molecule 1)
- Constantly survey the brain parenchyma
- Turn over slowly throughout life
Functions:
- Immune surveillance: Phagocytose debris and pathogens
- Synaptic pruning: Eliminate excess synapses during development
- Neuroinflammation: Release pro-inflammatory cytokines when activated
- Support neuronal health: Produce neurotrophic factors
Astrocytes:
- Reactive astrocytes surround amyloid plaques
- Lose normal functions ( glutamate recycling)
- Contribute to neuroinflammation
- Form astrocytic plaques (Aβ accumulation)
Microglia:
- Chronic activation around plaques
- Create neurotoxic inflammatory environment
- TREM2 variants increase AD risk
- Failed clearance of Aβ and tau
Oligodendrocytes:
- Myelin degeneration precedes clinical symptoms
- Vulnerable to oxidative stress
- Loss contributes to white matter atrophy
Astrocytes:
- Reactive astrocytes in substantia nigra
- Impaired dopamine metabolism
- May spread α-synuclein pathology
Microglia:
- Chronic activation in substantia nigra
- NADPH oxidase-mediated oxidative stress
- Contribute to dopaminergic neuron death
Oligodendrocytes:
- Myelin abnormalities in PD brains
- α-Synuclein accumulation in oligodendrocytes
- Vulnerable to iron-induced oxidative stress
Astrocytes:
- Loss of glutamate transporters (EAAT2)
- Excitotoxicity due to glutamate accumulation
- Non-cell autonomous toxicity to motor neurons
Microglia:
- Activated in spinal cord and motor cortex
- Pro-inflammatory cytokine release (TNF-α, IL-1β)
- Mutant SOD1 in microglia contributes to disease
Oligodendrocytes:
- Pre-motor neuron degeneration
- Failed remyelination in progressive stages
- Oligodendrocyte precursor cells fail to differentiate
Astrocytic processes ensheath synapses, forming a tripartite synapse:
- Pre-synaptic neuron
- Post-synaptic neuron
- Perisynaptic astrocyte
Astrocytes detect neurotransmitter release and modulate synaptic transmission.
Astrocytes regulate cerebral blood flow by:
- Sensing neural activity through calcium signals
- Releasing vasoactive substances (prostaglandins, epoxyeicosatrienoic acids)
- Causing vasodilation of nearby arterioles
Astrocytes release signaling molecules:
- Glutamate (via vesicles)
- D-serine (co-agonist for NMDA receptors)
- ATP/adenosine (modulates synaptic plasticity)
- EAAT2 modulators: Enhance glutamate uptake
- A1 adenosine receptor antagonists: Block astrocyte-mediated toxicity
- GFAP inhibitors: Reduce reactive astrogliosis
- TREM2 agonists: Enhance phagocytosis
- CD33 inhibitors: Reduce amyloid clearance blockade
- Anti-inflammatory drugs: Modulate neuroinflammation
- Remyelination promoters: LINGO-1 antagonists
- MBP stabilizers: Protect existing myelin
- OPC recruitment: Enhance oligodendrocyte precursor differentiation