Nat Rev Drug Discov: [Review] The role and therapeutic value of astrocytes in neurological diseases

Astrocytes are the most abundant glial cells in the central nervous system (CNS) and perform a variety of functions
in health and disease.
Astrocytes regulate glutamate and ionic homeostasis, cholesterol and sphingolipid metabolism, and respond to environmental factors, all of which are associated with
neurological disorders.
Astrocytes also exhibit significant heterogeneity, regulating astrocyte positions and cell-cell interactions
in the CNS by developmental programs and stimulating-specific cellular responses.

An article published in February 2022 by Francisco J Quintana of the Broad Institute of Technology at MIT and Harvard University in the journal Nature Reviews Drug Discovery focused on the role of astrocytes in neurological diseases and their potential
as targets for therapeutic intervention.
In addition, a concise nomenclature of astrocyte subsets is proposed, emphasizing the role
of astrocyte-specific subsets in neurological diseases.

1

Overview and classification of astrocytes

Astrocytes were first proposed
in the 19th century by Rudolf Virchow.
Ten years later, Camillo Golgi visualized the morphology of astrocytes using silver chromate staining technology, proposing the concept of
glial cells acting as brain "glue".
Astrocytes were quickly divided into two basic morphological subtypes: protoplasmic and fibrous
.
Protoplasmic astrocytes occur mainly in gray matter, while fibrous astrocytes are commonly found in
white matter.
Santiago Ramón y Cajal took these subtypes and further revealed the different morphologies
of astrocytes in the human cerebellum.

Astrocytes are heterogeneous
.
New molecular techniques have identified astrocyte subsets
based on their molecular characteristics and/or function (promoting or inhibiting CNS inflammation or neurodegeneration).
These subsets are divided into two categories: developmental program-driven astrocyte subsets (DIA subsets) and stimulus-induced astrocyte subsets (SIA subsets).

Figure 1: Astrocyte subsets and plasticity

2

Function of astrocytes

Astrocytes are involved in key processes related to CNS homeostasis, including neurotransmitter circulation, ion balance, energy metabolism, regulation of synaptogenesis and synaptic transmission, and maintenance of the blood-brain barrier
.

CNS inflammation

Astrocytes are involved in CNS inflammation and have pro-inflammatory and anti-inflammatory activities
.
Since astrocytes interact with other cells and molecules in the CNS, they secrete various cytokines, chemokines, and neuromodulatory molecules
.
In an acute EAE B6 mouse model, a decrease in reactive astrocytes increased disease severity and CNS inflammation
.
In contrast, in the NOD mouse EAE model, selective reduction of reactive astrocytes during chronic progression improves disease pathogenesis and limits the recruitment and activation
of microglia and monocytes.
The opposite role of astrocytes in CNS inflammation highlights their functional heterogeneity
.

Figure 2: Role of astrocytes in CNS inflammation

Glutamate homeostasis

Glutamate is the most prevalent excitatory neurotransmitter in the CNS, however excess glutamate triggers neuronal death, a process known as excitotoxicity
.
Astrocytes clear extracellular glutamate from the synaptic cleft via the high-affinity glutamate transporters excitatory amino acid transporters 1 (EAAT1) and EAAT2, which play key roles
in glutamate homeostasis, synaptic plasticity, and neuronal survival.
Thus, impaired glutamate uptake by astrocytes can lead to neuronal excitotoxicity, which is often associated with
neurodegeneration.

In Alzheimer's disease, the accumulation of amyloid β (Aβ) in the brain regulates glutamate uptake
by astrocytes by inhibiting EAAT2.
This leads to overactivation of neurons expressing glutamate receptors, increases intracellular Ca2+, promotes neurological dysfunction
.

Image

Figure 3: Targeted study of astrocyte signaling in Alzheimer's disease

Ion homeostasis

Astrocytes regulate neuronal excitability
by promoting K+ absorption and buffering in the brain.
Astrocytes express a variety of K+ channels, effectively removing K+ ions from extracellular fluid, a process called K+ space buffering
.
Thus, astrocyte K+ channel dysfunction can lead to neuronal damage, leading to neurodegeneration
.

In Huntington's disease, mutant huntingtin protein (mHTT) in astrocytes impair the expression
of excitatory amino acid transporter 2 (EAAT2) and the K+ ion channel Kir4.
1.
Decreased glutamate transporter levels resulted in enhanced
mGlu2/3-mediated Ca2+ signaling.
The induced increase in astrocyte Ca2+ signal is followed by a loss
of spontaneous Ca2+ signaling.
Elevated levels of extracellular K+ and glutamate lead to neuronal hyperexcitation and the development of
neurodegeneration.

Figure 4: Targeting astrocyte signaling in Huntington's disease

energy metabolism

Astrocytes provide neurons with their energy needs
by supporting lactate transfer, called astrocyte-neuronal lactate shuttle.
High levels of extracellular K+, glutamate uptake, and intracellular Ca2+ trigger astrocyte lactate release
.
Astrocyte metabolic dysfunction is associated with neurodegenerative diseases, including MS, AD, PD, and HD
.
For example, lactosylceramide-mediated astrocyte sphingolipid metabolism regulates metabolic interactions between astrocytes and neurons, which is the pathogenesis of EAE and MS
.

Neurotoxicity

The neurotoxic activity of astrocytes may involve multiple triggers, astrocyte subsets, and effector mechanisms
.
C3+ neurotoxic astrocyte subsets induced by microglia production of complement factor C1q, tumor necrosis factor (TNF), and IL-1α stimulation can induce neuronal death
.
Long-chain saturated lipids, synthesized by elongation of ultra-long-chain fatty acid protein 1 and secreted in lipid granules, are neurotoxic factors
secreted by astrocytes.

3

The role of astrocytes in psychiatric disorders

Dysregulation of astrocyte function, such as regulation of neuronal activity, release of neurotransmitters, and processes associated with synaptic pruning, are all associated with
neuropsychiatric disorders.
During development, astrocytes regulate synaptic pruning
through microglia.
For example, astrocytes promote synaptic pruning of the developing visual system through IL-33-mediated mechanisms, associated
with microglia-dependent synaptic pruning.
In addition, complement produced by astrocytes has been shown to trigger microglia-dependent pruning to remodel neural circuits
.

Cytokines produced by astrocytes are associated
with depression and anxiety-like behavior.
For example, adenosine signaling in amygdala astrocytes promotes anxiety-related phenotypes
in a regionally and synapse-specific manner.
Targeting astrocyte cytokine production may provide new treatment options
for depression and related disorders.

summary

A major challenge with astrocyte-targeted therapy is the heterogeneity of astrocytes in health and disease
.
Different astrocyte subsets show significant differences
between CNS region distribution, disease, or disease states.

Interestingly, some of the pathogenesis associated with astrocytes is common in a variety of neurological disorders, including neurotoxicity and abnormal regulation of extracellular glutamate levels, K+ ion circulation, or lactate shuttle defects
.
Regulation of these common astrocyte activity dysregulated pathways may provide targets for the treatment of multiple neurological disorders driven by astrocytes
.

Original source:

Astrocytes are the most abundant glial cells in the central nervous system (CNS) and perform a variety of functions
in health and disease.
Astrocytes regulate glutamate and ionic homeostasis, cholesterol and sphingolipid metabolism, and respond to environmental factors, all of which are associated with
neurological disorders.
Astrocytes also exhibit significant heterogeneity, regulating astrocyte positions and cell-cell interactions
in the CNS by developmental programs and stimulating-specific cellular responses.

Image

An article published in February 2022 by Francisco J Quintana of the Broad Institute of Technology at MIT and Harvard University in the journal Nature Reviews Drug Discovery focused on the role of astrocytes in neurological diseases and their potential
as targets for therapeutic intervention.
In addition, a concise nomenclature of astrocyte subsets is proposed, emphasizing the role
of astrocyte-specific subsets in neurological diseases.

1

Overview and classification of astrocytes

Astrocytes were first proposed
in the 19th century by Rudolf Virchow.
Ten years later, Camillo Golgi visualized the morphology of astrocytes using silver chromate staining technology, proposing the concept of
glial cells acting as brain "glue".
Astrocytes were quickly divided into two basic morphological subtypes: protoplasmic and fibrous
.
Protoplasmic astrocytes occur mainly in gray matter, while fibrous astrocytes are commonly found in
white matter.
Santiago Ramón y Cajal took these subtypes and further revealed the different morphologies
of astrocytes in the human cerebellum.

Astrocytes are heterogeneous
.
New molecular techniques have identified astrocyte subsets
based on their molecular characteristics and/or function (promoting or inhibiting CNS inflammation or neurodegeneration).
These subsets are divided into two categories: developmental program-driven astrocyte subsets (DIA subsets) and stimulus-induced astrocyte subsets (SIA subsets).

Image

Figure 1: Astrocyte subsets and plasticity

2

Function of astrocytes

Astrocytes are involved in key processes related to CNS homeostasis, including neurotransmitter circulation, ion balance, energy metabolism, regulation of synaptogenesis and synaptic transmission, and maintenance of the blood-brain barrier
.

CNS inflammation

Astrocytes are involved in CNS inflammation and have pro-inflammatory and anti-inflammatory activities
.
Since astrocytes interact with other cells and molecules in the CNS, they secrete various cytokines, chemokines, and neuromodulatory molecules
.
In an acute EAE B6 mouse model, a decrease in reactive astrocytes increased disease severity and CNS inflammation
.
In contrast, in the NOD mouse EAE model, selective reduction of reactive astrocytes during chronic progression improves disease pathogenesis and limits the recruitment and activation
of microglia and monocytes.
The opposite role of astrocytes in CNS inflammation highlights their functional heterogeneity
.

Image

Figure 2: Role of astrocytes in CNS inflammation

Glutamate homeostasis

Glutamate is the most prevalent excitatory neurotransmitter in the CNS, however excess glutamate triggers neuronal death, a process known as excitotoxicity
.
Astrocytes clear extracellular glutamate from the synaptic cleft via the high-affinity glutamate transporters excitatory amino acid transporters 1 (EAAT1) and EAAT2, which play key roles
in glutamate homeostasis, synaptic plasticity, and neuronal survival.
Thus, impaired glutamate uptake by astrocytes can lead to neuronal excitotoxicity, which is often associated with
neurodegeneration.

In Alzheimer's disease, the accumulation of amyloid β (Aβ) in the brain regulates glutamate uptake
by astrocytes by inhibiting EAAT2.
This leads to overactivation of neurons expressing glutamate receptors, increases intracellular Ca2+, promotes neurological dysfunction
.

Image

Figure 3: Targeted study of astrocyte signaling in Alzheimer's disease

Ion homeostasis

Astrocytes regulate neuronal excitability
by promoting K+ absorption and buffering in the brain.
Astrocytes express a variety of K+ channels, effectively removing K+ ions from extracellular fluid, a process called K+ space buffering
.
Thus, astrocyte K+ channel dysfunction can lead to neuronal damage, leading to neurodegeneration
.

In Huntington's disease, mutant huntingtin protein (mHTT) in astrocytes impair the expression
of excitatory amino acid transporter 2 (EAAT2) and the K+ ion channel Kir4.
1.
Decreased glutamate transporter levels resulted in enhanced
mGlu2/3-mediated Ca2+ signaling.
The induced increase in astrocyte Ca2+ signal is followed by a loss
of spontaneous Ca2+ signaling.
Elevated levels of extracellular K+ and glutamate lead to neuronal hyperexcitation and the development of
neurodegeneration.

Image

Figure 4: Targeting astrocyte signaling in Huntington's disease

energy metabolism

Astrocytes provide neurons with their energy needs
by supporting lactate transfer, called astrocyte-neuronal lactate shuttle.
High levels of extracellular K+, glutamate uptake, and intracellular Ca2+ trigger astrocyte lactate release
.
Astrocyte metabolic dysfunction is associated with neurodegenerative diseases, including MS, AD, PD, and HD
.
For example, lactosylceramide-mediated astrocyte sphingolipid metabolism regulates metabolic interactions between astrocytes and neurons, which is the pathogenesis of EAE and MS
.

Neurotoxicity

The neurotoxic activity of astrocytes may involve multiple triggers, astrocyte subsets, and effector mechanisms
.
C3+ neurotoxic astrocyte subsets induced by microglia production of complement factor C1q, tumor necrosis factor (TNF), and IL-1α stimulation can induce neuronal death
.
Long-chain saturated lipids, synthesized by elongation of ultra-long-chain fatty acid protein 1 and secreted in lipid granules, are neurotoxic factors
secreted by astrocytes.

3

The role of astrocytes in psychiatric disorders

Dysregulation of astrocyte function, such as regulation of neuronal activity, release of neurotransmitters, and processes associated with synaptic pruning, are all associated with
neuropsychiatric disorders.
During development, astrocytes regulate synaptic pruning
through microglia.
For example, astrocytes promote synaptic pruning of the developing visual system through IL-33-mediated mechanisms, associated
with microglia-dependent synaptic pruning.
In addition, complement produced by astrocytes has been shown to trigger microglia-dependent pruning to remodel neural circuits
.

Cytokines produced by astrocytes are associated
with depression and anxiety-like behavior.
For example, adenosine signaling in amygdala astrocytes promotes anxiety-related phenotypes
in a regionally and synapse-specific manner.
Targeting astrocyte cytokine production may provide new treatment options
for depression and related disorders.

summary

A major challenge with astrocyte-targeted therapy is the heterogeneity of astrocytes in health and disease
.
Different astrocyte subsets show significant differences
between CNS region distribution, disease, or disease states.

Interestingly, some of the pathogenesis associated with astrocytes is common in a variety of neurological disorders, including neurotoxicity and abnormal regulation of extracellular glutamate levels, K+ ion circulation, or lactate shuttle defects
.
Regulation of these common astrocyte activity dysregulated pathways may provide targets for the treatment of multiple neurological disorders driven by astrocytes
.

Original source:

Lee， HG.
， Wheeler， M.
A.
& Quintana， F.
J.
Function and therapeutic value of astrocytes in neurological diseases.
Nat Rev Drug Discov 21， 339–358 (2022).
https：//doi.
org/10.
1038/s41573-022-00390-x.