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Astrocytes are the main glial cell type in the central nervous system (CNS) and are important regulators
of brain function.
The transition from resting astrocytes to reactive astrocytes in the pathological microenvironment is a common feature
of multiple neurodegenerative diseases (NDs).
But it is now recognized that reactive astrocytes are also heterogeneous, with multiple subsets
of reactive astrocytes present in different NDs.
Allen of the Salk Institute of Biology published an article in Nature Reviews Neuroscience to introduce the changes in the transcriptome, proteome, physiological characteristics and functions of astrocytes in NDs, as well as the role of astrocytes in the pathology of NDs, and explored potential strategies
for the treatment of NDs against astrocytes in the future.
1
Physiological changes in astrocytes
Astrocytes maintain synaptic homeostasis through a variety of physiological functions, including neurotransmitter uptake and recovery, energy substance supply, lipid synthesis, glial transmitter release, extracellular potassium levels and maintenance of water balance.
In NDs, these physiological functions change with the development of neurodegenerative degeneration (Figure 1).
Figure 1: Astrocyte physiological changes associated with neurodegenerative disease
.
The glymphatic system dependent on astrocytes aquaporin 4 (AQP4), as well as the astrocytes' own lysosomal degradation, are important pathways
to remove these abnormal proteins.
Under pathological conditions of NDs, protein polymers affect astrocytes and disrupt the clearance pathway, resulting in obstruction
of abnormal protein clearance.
The calcium signaling of calcium homeostasis astrocytes is related
to its own multiple physiological functions and their interaction with synapses.
Dysregulation of calcium signaling in astrocyte cells has a detrimental effect on synaptic function, participates in the initiation and development of NDs, and its mechanisms include abnormal activation
of transmitter receptors and ion channels.
Calcium homeostasis imbalance in astrocytes was found in ALS, PD, HD, and AD, and its trigger was not only disease-specific, but also varied with pathological progression
.
Synaptic activity and the uptake and release of transmitters by ionic homeostatic astrocytes are related to intracellular calcium levels, and GLT1, sodium-calcium exchange protein (NCX), potassium channel Kir4.
1, three functionally interrelated calcium homeostasis-related molecules, participate in the development of
neurodegenerative degeneration by affecting synaptic activity and ion homeostasis.
The glutamate transporters GLT-1 and GLAST on astrocytes are responsible for the uptake and recovery
of about 80% of glutamate in the synaptic cleft.
Decreased GLT1 expression is a common feature of NDs and can cause changes in extracellular glutamate levels, leading to excitotoxicity and neurodegeneration
.
In addition, the release of other gliotransmitters, including ATP, D-serine, and GABA, is also increased in AD, inducing pathological changes
in synaptic transmission and cognitive performance.
Energy and lipid metabolism neurons rely on astrocytes to obtain metabolic substrates, and the "astrocytes-neuron-lactate shuttle" is a typical mechanism, and glutamate transporters are at the heart of this mechanism, and astrocytes convert glucose into lactic acid to power neurons
.
There are disorders of energy metabolism in AD, PD, ALS, and HD, and increased glucose uptake and metabolism exert neuroprotective effects
.
In addition, neurons also rely on astrocytes to provide cholesterol, astrocytes APOE mediates the secretion of cholesterol, and cholesterol metabolism dysfunction is also an important pathological feature of
NDs.
Glucose metabolism is closely related to lipid metabolism, and changes in glucose metabolism in neurodegenerative degeneration may be related to
changes in lipid metabolism.
2
Effects of ND genetic risk on astrocytes
Although NDs share many common characteristics, different NDs can be driven by unique genetic and environmental factors, affect different brain regions, and exhibit different physiological changes.
The impact of NDs-associated gene mutations on specific cell types depends on the type of disease (Figure 2), and the resulting astrocytes changes are one of the
main inducing factors for disease onset.
Figure 2: Astrocytes and neuronal expression of genes associated with the risk of NDs
with excitotoxicity.
Gene mutations expressed by a variety of cells, including astrocytes, are the most common type of
mutation in NDs.
For example, HTT mutations in HD, PINK1, PRKN, LRRK2 mutations in PD, APP, PSEN1, PSEN2, and APOE mutations in AD all occur in neurons and astrocytes, which can affect astrocytes function and disrupt astrocytes-neuron communication
.
The gene mutation tau gene (MAPT) enriched in neurons is specifically expressed in neurons, and its mutation causes excessive phosphorylation of tau protein, leading to the formation
of nerve fiber tangles.
Astrocytes produce a variety of biological responses to filamentous or insoluble tau protein oligomers, including increased immune response and cytokine release, morphological changes, loss of synaptic support, etc.
, which are defined as aging-related tau astrocytic lesions, which are typical pathological mechanisms
of frontotemporal dementia and AD.
3
Transcriptome and proteomics of astrocytes
There are changes
in gene and protein networks in NDs for multiple cell types.
, which disrupt the synaptic environment and weaken
the support for synapses.
In NDs, the upregulation of the complement cascade and immune signals of astrocytes is more intense relative to the physiological aging process, and support for synapses is weakened more pronounced
.
Transcriptome studies of astrocytes in different NDs have shown both common and disease-specific changes in different diseases
.
For example, the enhancement of inflammatory signaling and the intensification of immune regulation in AD and ALS astrocytes are more prominent
than in HD and PD.
The heterogeneity of brain regions in astrocytes may explain why specific brain regions are affected
to varying degrees in different NDs.
In addition, there are a large number of different astrocyte reactivity states in NDs, which are related to
disease stage and pathological process.
The most typical of these are "disease-associated astrocytes" (DAAs)
found and defined in the hippocampus, an AD model animal.
Studies have shown that in aging, or NDs, DAAs increase and are spatially localized close to pathology (Figure 3).
Figure 3.
Transformation of astrocytes molecular phenotype in aging and disease
that occur at post-transcriptional levels.
Labeling proteins in cell type-specific ways, such as atypical amino acid consolidation and biotin proximity labeling, can identify cell types
most likely to cause proteome changes.
The spatial localization of protein and RNA changes helps to resolve the heterogeneous responses of astrocytes in neurodegenerative degeneration, and whether these responses are dependent on specific pathologies
.
4
Therapeutic approach to intervention
Multiple therapeutic strategies for astrocytes in neurodegenerative degeneration have been proposed.
These strategies include pharmacological approaches based on astrocytes enrichment targets, targeting pathways in astrocytes using drugs or genetic means, targeting transcription factors to modify the expression of specific genes or proteins in astrocytes, transplanting healthy astrocytes into areas affected by neurodegeneration, or converting astrocytes into neurons to replace damaged cells (Figure 4).
Figure 4.
Therapeutic strategies targeting astrocytes in neurodegenerative diseases
summary
Gene mutations, changes in RNA and protein levels, and changes in environmental stress lead to changes in astrocytes function, disrupt the central nervous system environment, lead to neurodegeneration, and promote the pathological development of
NDs.
Combining RNA sequencing technology with high-throughput proteomics, phosphorylated proteomics, lipidomics and metabolomics, and spatial analysis to resolve the regional heterogeneity of astrocytes, the heterogeneity of reactive astrocytes, and the temporal dynamics of gene and protein expression associated with pathological processes will facilitate the treatment of NDs targeting astrocytes
.
【References】
1.
Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders.
(2022) Nature Reviews.
Neuroscience.
The images in the article are from references
