Glutamate transport dysfunction in neurological disorders : from cellular models to in vivo neuroimaging

Abstract

For decades, evaluating the neuropathology of Alzheimer’s disease (AD) was only possible trough post-mortem investigation of the brain tissue. Recent advances in positron emission tomography (PET) imaging allow for assessing the living brain in a non-invasive manner. Indeed, the use of selective PET radiotracers permits the specific examination of amyloid-β (Aβ) and tau – the AD core pathology. However, there is a consensus regarding the need for developing innovative PET radiotracers to detect AD in the initial preclinical stages. With this mind, this thesis aimed at investigating early pathophysiological changes in AD with PET imaging. For doing so, we first critically revised the Aβ oligomers (AβOs) literature – the main early toxic species of Aβ. Second, we optimised and validated a method for synthetic AβOs quality control. Third, we demonstrated that synthetic AβOs cause detectable [18F]FDG PET brain hypometabolism in mice, which seems related to astrocyte reactivity. Fourth, we searched the literature for potential PET radiotracer candidate molecules with affinity to astrocyte glutamate transporters. Fifth, we designed and tested the first generation of PET radiotracers targeting glutamate transporters. Finally, we used the knowledge acquired in PET imaging research in AD to propose strategies to understand COVID-19 effects in the brain. In summary, theoretical articles (reviews, letters, and others) produced in this thesis helped to guide basic and clinical research in AD and COVID-19. In addition, our experimental findings advanced our knowledge regarding AβOs as triggers of [18F]FDG PET brain hypometabolism and provided the first generation of an innovative class of PET radiotracers targeting astroglial glutamate transporter.