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Contribution de la voie Wnt dans la stabilité de la barrière hémato-encéphalique

Abstract : Dementia is characterized by a progressive deterioration of mental capacity that inevitably compromises independent living. Advancing age is the main risk factor, and due to the aging of the world population and lack of effective treatments, the number of affected individuals, estimated at 50 million worldwide, is anticipated to triple by 2050 at a cost approaching 4 trillion dollars. Recent studies tend to show a crucial role of vascular dysfunction in dementia pathologies. Indeed, a large autopsy-based neuropathological study has revealed that 80% of patients diagnosed with Alzheimer’s disease (AD) exhibit vascular pathology. However, the cellular and molecular mechanisms underlying vascular dysfunction and alteration of the blood brain barrier (BBB) integrity associated with dementia and AD remain to be elucidated. Body of evidences point out the Wnt pathway role in the maintenance of BBB integrity. The laboratory recently identified an E3-ubiquitin-ligase, PDZRN3 acting like Wnt non-canonical pathway modulator in endothelial cells repressing canonical Wnt pathway. This ubiquitin-ligase is involved in vascular permeability, making it a promising modulatory target to act upon alterations of the BBB integrity. We then hypothesized that: BBB is destabilized in the early onset of dementia & AD, keeping EC in a differentiated “barrier” state through Wnt signaling modulation should modulates early onset of dementia. We have generated Pdzrn3 inducible EC knockout (iECKO) mice and submitted them to gradual cerebral hypoperfusion by implanting ameroïd constrictors on both common carotid arteries. While memory performance of wild-type littermates is impaired under hypoperfusion, that of iECKO mice is preserved. Importantly, our data show that iECKO mice exhibit a significant decrease in the number of brain lesions (microinfarctions) as well as reduced neuronal loss in the CA1 hippocampal region known to play a crucial role in spatial recognition memory. Conversely, endothelial PDZRN3 overexpression (iECOE) produces phenotypes opposite to those of Pdzrn3-deleted mice (iECKO) with a clear deterioration of memory function associated with increased BBB leakage, brain lesions, hippocampal neuronal loss and inflammation compared to controls. We also wanted to investigate the impact of endothelial deletion of Pdzrn3 in AD. To this end, we have generated and validated a dedicated triple transgenic mouse model by crossing APP/PS1, AD mouse model with with Pdzrn3 iECKO mice to generate APP/PS1;Pdzrn3 iECKO colonies. Strikingly, our findings point to a significant decrease of Aβ-deposits at 6 months in APP/PS1;Pdzrn3 iECKO compared to APP/PS1 littermate control mice. At 8 months, APP/PS1 littermate controls appears severely impaired in a spatial recognition memory paradigm whereas APP/PS1;Pdzrn3 iECKO performed as well as non-demented age-matched Pdzrn3 iECKO and littermate controls.
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Florian Gueniot. Contribution de la voie Wnt dans la stabilité de la barrière hémato-encéphalique. Médecine humaine et pathologie. Université de Bordeaux, 2019. Français. ⟨NNT : 2019BORD0386⟩. ⟨tel-02937442⟩

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