Biology subjects

Paumier, A.

Publications and source records attributed to Paumier, A..

3 recordsLinked to original sources

bioRxiv2025

Astrocyte SEMA3C reduction improves Rett Syndrome phenotypes

Astrocytes support neuronal function during development through secreted proteins, yet how astrocyte-secreted cues are altered in disease states and contribute to neurodevelopmental disorders remains poorly defined. Rett syndrome (RTT) is a regressive neurodevelopmental disorder characterized by motor, sensory, and cognitive impairments. Here, we identify the class 3 semaphorin SEMA3C as an astrocyte-secreted protein that contributes to RTT pathology. We show that Sema3c expression is elevated in astrocytes in vivo in RTT model mice and find that SEMA3C is sufficient to inhibit cortical neuron dendrite outgrowth. Normalization of astrocyte SEMA3C levels in female RTT model mice rescues dendritic arborization deficits, restores synaptic activity, and improves visual acuity and motor behavior. Mechanistically, both SEMA3C and RTT astrocyte conditioned media inhibit dendrite outgrowth through PLXND1-dependent signaling. Together, these findings identify astrocyte-secreted SEMA3C as a contributor to RTT pathology and highlight SEMA3C and PLXND1 signaling as potential therapeutic targets in neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Astrocyte transcriptomic analysis identifies glypican 5 downregulation as a contributor to synaptic dysfunction in Alzheimer disease models

Synaptic dysfunction is an early feature in Alzheimers disease (AD) and correlates with cognitive decline. Astrocytes are essential regulators of synapses, impacting synapse formation, maturation, elimination and function. To understand if synapse-supportive functions of astrocytes are altered in AD, we used astrocyte BacTRAP mice to generate a comprehensive dataset of hippocampal astrocyte transcriptional alterations in two mouse models of Alzheimers pathology (APPswe/PS1dE9 and Tau P301S), characterizing sex and age-dependent changes. We found that astrocytes from both models downregulate genes important for synapse regulation and function such as the synapse-maturation factor Glypican 5. This transcriptional signature is shared with human post-mortem AD patients. Manipulating a key component of this signature by in vivo overexpression of Glypican 5 in astrocytes is sufficient to prevent early synaptic dysfunction and improve spatial learning in APPswe/PS1dE9 mice. These findings open new avenues to target astrocytic factors to mitigate AD synaptic dysfunction.

neuroscience↗

bioRxiv2021

Astrocyte-neuron interplay is critical for Alzheimer's disease pathogenesis and is rescued by TRPA1 channel blockade

BackgroundThe sequence of cellular dysfunctions in preclinical Alzheimers disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimers disease in both humans and mouse models. The most common hypothesis describes amyloid {beta} accumulation as the triggering factor of the disease but the effects of such accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid {beta}-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection brought by an early chronic pharmacological inhibition of TRPA1 channel on Alzheimers disease progression. MethodsWe administered a specific inhibitor of TRPA1 channel (HC030031) intraperitoneally from the onset of amyloid {beta} overproduction in the APP/PS1-21 mouse model of Alzheimers disease. We characterized short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade on Alzheimers disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels. ResultsOur results revealed that the first observable disruptions in the Alzheimers disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction, preserves structural synaptic integrity and strengthens the glial plaque barrier. These protective effects preserved spatial working-memory in this Alzheimers disease mouse model. ConclusionThe toxic effect of amyloid {beta} on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimers disease progression. TRPA1 blockade prevent irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.

neuroscience↗