INVOLVEMENT OF ASTROCYTIC TRPA1 IN THE DISRUPTION OF NEURON-ASTROCYTE INTERACTIONS INVOLVED IN THE INITIATION OF ALZHEIMER'S DISEASE

The recurrent failure of therapeutic strategies in Alzheimer's disease (AD) is partly due to the fact that they target late stages of the disease. We have discovered a promising new neuroprotective therapeutic target in the early and asymptomatic phase, the transient receptor potential ankyrin-1 channel (TRPA1). In the hippocampus, this astrocytic channel is activated by β-amyloid peptide (Aβ), which accumulates during the course of the disease. This phenomenon causes an abnormal increase of calcium activity in astrocytes, leading to a toxic hyperactivity of neighbouring neurons, and progressive and irreversible synapses degeneration. We showed that a daily pharmacological treatment with a TRPA1 inhibitor in a mouse model protects synapses from the toxic effect of Aβ and prevents memory loss. The aim of this project is to understand how this astrocytic toxicity induces critical synaptic dysregulation that leads to memory disorders. We implemented high resolution microscopy and electrophysiological recordings in neurons and astrocytes in order to assess the impact of Aβ on various aspects of neuron-astrocyte communication. We showed that Aβ-dependent TRPA1-activation elicits an increase of gliotransmitters release (involving D-serine and glutamate), and a disturbance in the astrocytic glutamate uptake involving glutamate transporters-1 (GLT1). This functional disruption of the astrocytic glutamate transporter current is coupled with a mis-localization of these transporters around the synapses. Therefore, our data highlight new mechanisms occurring in the pathology initiation, leading to a glutamate dyshomeostasis and the subsequent critical neuronal hyperactivity. They contribute to understand early pathophysiological processes occurring in the early and reversible phases of AD.