Mechanisms of amyloid- β peptide-dependant TRPA1 channel activation and its role in astrocytic glutamate reuptake during the onset of Alzheimer's disease.

Tuesday October the 27th 2026, Apolline Pierre will defend hes PhD entitled "Mechanisms of amyloid- β peptide-dependant TRPA1 channel activation and its role in astrocytic glutamate reuptake during the onset of Alzheimer's disease".

This PhD was carried out under the supervision of Mireille Albrieux of the team "Neuropathologies and Synaptic Dysfunctions" of the GIN.

Jury :

- David Blum, Inserm Délégation Nord Ouest, reviewer
- Karine Cambon, CEA Paris-Saclay, reviewer
- Julien Dupuis, Inserm Délégation Nouvelle Aquitaine, examiner
- Emmanuelle Tilltet, Université Grenoble Alpes, examiner
- Mireille Albrieux, Université Grenoble Alpes, PhD supervisor

Abstract :

The recurring failure of therapeutic strategies in Alzheimer’s disease (AD) can be partly explained by the fact that they target the advanced stages of the disease. We have discovered a promising new neuroprotective therapeutic target that acts on the early, asymptomatic stage of AD: TRPA1 (Transient Receptor Potential Ankyrin-1) channel. In the hippocampus, this astrocytic channel is activated by the amyloid-β (Aβ) peptide, causing an abnormal increase in calcium activity within astrocytes, leading to toxic hyperactivity in neighbouring neurons. We have demonstrated that inhibition of TRPA1, via daily pharmacological treatment in a mouse model of AD, protects synapses and prevents memory loss. The aim of my thesis is to determine how Aβ activates TRPA1 and to understand how this astrocytic activation induces critical neuronal hyperactivity leading to neurodegeneration. To this end, we  have investigated the mechanism by which TRPA1 is activated by the Aβ peptide using its heterologous expression in Xenopus oocytes and real-time recordings of the currents generated by TRPA1 using the ‘two-electrode voltage-clamp’ technique (TEVC). In parallel, using high-resolution microscopy and electrophysiological techniques on neurons and astrocytes, we assessed the impact of the Aβ peptide on various aspects of neuron-astrocyte communication. We therefore observed a rapid, marked and reversible activation of TRPA1 induced by the Aβ peptide in a dose-dependent manner. Furthermore, the addition of a specific inhibitor of TRPA1 persistently inhibits this activation via a competitive mechanism, revealing a direct action of the peptide on the channel. This activation of the TRPA1 channel, which is dependent on the Aβ peptide, causes a disruption in astrocytic glutamate transport involving type 1 glutamate transporters (GLT1). Inhibition of the TRPA1 channel does not restore GLT1 function, but alters its localisation and mobility at the synapses, which appears to prevent the onset of neuronal hyperactivity. Thus, our data highlight new mechanisms involved in the onset of the disease, leading to glutamate dyshomeostasis and the critical neuronal hyperactivity that results from it. They contribute to our understanding of the early pathophysiological processes occurring during the initial and reversible phases of Alzheimer’s disease.