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Maladie d’Alzheimer et Syndrome d’Apnées du Sommeil : deux pathologies liées ? Etude des conséquences d’un stress hypoxique sur la cognition et la pathologie Tau dans le modèle murin transgénique THY-Tau22

Abstract : Alzheimer’s disease (AD) is a multifactorial neurodegenerative pathology constituting the first cause of dementia. At a cerebral level, two kinds of histopathological lesions are found in patients: amyloid deposits (extracellular aggregates of β-amyloid peptides: Aβ) and neurofibrillary degeneration (NFD). NFD consists in intraneuronal accumulation of paired helical filaments, mainly composed of aggregated and hyperphosphorylated Tau proteins. Aging is the main risk factor for AD. However, numerous environmental and genetic risk factors have also been identified. Since several years, some clinical studies have shown that sleep disorders breathing, and especially the sleep apnea syndrome (SAS) could be responsible of the conversion of mild cognitive impairment to AD. SAS could also be an aggravating factor for AD, with an increase of the cognitive decline seen in patients. In this context, many experimental studies have been interested in the consequences of an intermittent hypoxic stress on the amyloid pathology. More specifically, it has been shown that an intermittent hypoxic stress could potentiate Aβ synthesis both in vitro and in vivo. Nevertheless, the impact of an intermittent hypoxic stress on Tau pathology remains poorly investigated. As clinical studies in AD patients with a SAS have shown an increase of the cognitive decline, and that it is well known that NFD is correlated with the cognitive impairment in AD patients, we were interested to study the Tau pathology under hypoxia.Our objectives in this thesis were to evaluate the consequences of a hypoxic stress on memory and Tau protein in animals. We used the THY-Tau22 transgenic mouse model, overexpressing a human mutated Tau protein and presenting a progressive Tau pathology correlated with a memory impairment observable in behavioural tasks. The animals were submitted to hypoxia at different stages of the Tau pathology: the younger animals showed a moderate Tau pathology whereas the olders presented a major Tau pathology. Two different protocols were used in this work. The first one consisted in repeated acute hypoxias (inspired fraction of oxygen (FiO2): 8% for 1 hour, twice a week, for several months). The second one was a protocol of intermittent hypoxias (FiO2 comprised between 5% and 21%, 60 seconds cycles, 8 hours per day, for 2 weeks). We observed some unexpected results of hypoxic stress on memory and Tau pathology in our transgenic mice. More specifically, the THY-Tau22 mice exhibiting the stronger Tau pathology (the older animals) have shown an improvement of their memory after two weeks of intermittent hypoxia. This result goes against the clinical observations (aggravation of the cognitive decline of AD patients with a SAS), but is correlated in our model to a significant decrease of aggregated Tau protein in the hippocampi of our mice. We discuss here these results and their contribution to human pathology.
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Claire Alves Pires. Maladie d’Alzheimer et Syndrome d’Apnées du Sommeil : deux pathologies liées ? Etude des conséquences d’un stress hypoxique sur la cognition et la pathologie Tau dans le modèle murin transgénique THY-Tau22. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2015. Français. ⟨NNT : 2015LIL2S035⟩. ⟨tel-01883857⟩

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