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Astrocytic EphA4 signaling is important for the elimination of excitatory synapses in Alzheimer’s disease

ABSTRACT: Cell surface receptors, including erythropoietin-producing hepatocellular A4 (EphA4), are important in regulating hippocampal synapse loss, which is the key driver of memory decline in Alzheimer’s disease (AD). However, the cellular-specific roles and mechanisms of EphA4 are unclear. Here, we show that EphA4 expression is elevated in hippocampal CA1 astrocytes in AD conditions. Specific knockout of astrocytic EphA4 ameliorates excitatory synapse loss in the hippocampus in AD transgenic mouse models. Single-nucleus RNA sequencing analysis revealed that EphA4 inhibition specifically decreases a reactive astrocyte subpopulation with enriched complement signaling, which are characteristics associated with synapse elimination by astrocytes in AD. Importantly, astrocytic EphA4 knockout in an AD transgenic mouse model decreases complement tagging on excitatory synapses and excitatory synapses within astrocytes. These findings suggest an important role of EphA4 in the astrocyte-mediated elimination of excitatory synapses in AD and highlight the crucial role of astrocytes in hippocampal synapse maintenance in AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE284797 | GEO | 2024/12/29

REPOSITORIES: GEO

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Astrocytic EphA4 signaling is important for the elimination of excitatory synapses in Alzheimer’s disease

Project description:Cell surface receptors, including erythropoietin-producing hepatocellular A4 (EphA4), are important in regulating hippocampal synapse loss, which is the key driver of memory decline in Alzheimer’s disease (AD). However, the cellular-specific roles and mechanisms of EphA4 are unclear. Here, we show that EphA4 expression is elevated in hippocampal CA1 astrocytes in AD conditions. Specific knockout of astrocytic EphA4 ameliorates excitatory synapse loss in the hippocampus in AD transgenic mouse models. Single-nucleus RNA sequencing analysis revealed that EphA4 inhibition specifically decreases a reactive astrocyte subpopulation with enriched complement signaling, which are characteristics associated with synapse elimination by astrocytes in AD. Importantly, astrocytic EphA4 knockout in an AD transgenic mouse model decreases complement tagging on excitatory synapses and excitatory synapses within astrocytes. These findings suggest an important role of EphA4 in the astrocyte-mediated elimination of excitatory synapses in AD and highlight the crucial role of astrocytes in hippocampal synapse maintenance in AD.

2025-01-06 | PXD056771 | Pride

Complement C1q-dependent synapse elimination by astrocytes in a mouse model of Alzheimer's disease

Project description:Synapse loss and glial activation are hallmarks of Alzheimer's disease (AD). In Tau P301S transgenic mice, the complement pathway contributes to neuronal damage through microglial elimination of synapses. Here, we used unbiased proteomic profiling of postsynaptic density (PSD) fractions from Tau P301S mice in C1q-WT versus C1q knockout backgrounds to identify C1q-dependent changes at synapses. Integrative multi-omics analysis revealed that astrocyte- and microglia- specific proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. The same set of glial proteins (including C1q, C4, Gpnmb, and S100a4) is elevated in human AD synaptic fractions, and C4 levels are raised in cerebrospinal fluid (CSF) from AD patients. Besides microglia, we show that astrocytes contribute substantially to excitatory and inhibitory synapse engulfment in Tau P301S hippocampus. Based on staining of synapse markers within lysosomes, astrocytes showed preference for excitatory synapses whereas microglia preferred to engulf inhibitory synapse markers. Genetic deletion of C1q reduced astrocytic eating of excitatory and inhibitory synapses in Tau P301S mice, and rescued synapse density. Together, our data indicate that astrocytes contact and phagocytose synapses in a C1q- dependent manner and thereby contribute to synapse loss and neurodegeneration in AD.

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Astrocytic EphA4 signaling is important for the elimination of excitatory synapses in Alzheimer’s disease

Project description:Astrocytic EphA4 signaling is important for the elimination of excitatory synapses in Alzheimer’s disease

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Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus

Project description:Hippocampal synaptic plasticity is important for learning and memory formation. Homeostatic synaptic plasticity is a specific form of synaptic plasticity that is induced upon prolonged changes in neuronal activity to maintain network homeostasis. While astrocytes are important regulators of synaptic transmission and plasticity, it is largely unclear how they interact with neurons to regulate synaptic plasticity at the circuit level. Here, we show that neuronal activity blockade selectively increases the expression and secretion of IL-33 (interleukin-33) by astrocytes in the hippocampal cornu ammonis 1 (CA1) subregion. This IL-33 stimulates an increase in excitatory synapses and neurotransmission through the activation of neuronal IL-33 receptor complex and synaptic recruitment of the scaffold protein PSD-95. We found that acute administration of tetrodotoxin in hippocampal slices or inhibition of hippocampal CA1 excitatory neurons by optogenetic manipulation increases IL-33 expression in CA1 astrocytes. Furthermore, IL-33 administration in vivo promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, whereas conditional knockout of IL-33 in CA1 astrocytes decreases the number of excitatory synapses therein. Importantly, blockade of IL-33 and its receptor signaling in vivo by intracerebroventricular administration of its decoy receptor inhibits homeostatic synaptic plasticity in CA1 pyramidal neurons and impairs spatial memory formation in mice. These results collectively reveal an important role of astrocytic IL-33 in mediating the negative-feedback signaling mechanism in homeostatic synaptic plasticity, providing insights into how astrocytes maintain hippocampal network homeostasis.

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