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Microhémorragies cérébrales et cognition : impact fonctionnel à court, moyen et long termes dans un modèle murin

Abstract : In magnetic resonance imaging (MRI), cerebral microbleeds (CMB) appear as small, oval hypointense lesions corresponding to focal hemosiderin depositions. CMB prevalence in the general population is about 15,3%. Considered as biomarkers of small vessel diseases, CMBs are more frequent in people with cognitive impairments or dementia with a prevalence of 23% in A.lzheimer disease (AD). Several population-based studies show an effect of CMBs on cognitive functions. They could have a key role in AD pathophysiology creating a link between amyloid and vascular hypothesis. However, their cognitive impact in AD remains unclear. A new murine model of cortical microhemorrhage (CMH) has been developed in order to study with a multimodal approach, the functional impact of the cortical lesion: i) in Wild type (WT) mice without any underlying pathology, ii) in transgenic J20 mice expressing the human mutated amyloid protein precursor (APP). The effect of a pharmacological modulation by atorvastatin was also studied in this model._x000D_10 weeks-old male mice, WT and APP were operated by stereotaxic injection of collagenase 0.8 µUI/µL to induce the CMH. 24 hours after surgery, mice underwent MRI acquisition (T2* sequence) to visualize the bleeding. Mice were divided into sham, CMH and CMH treated by atorvastatin groups. Atorvastatin was administered by mixing a tablet into the mice’s standard chow at a dose of 5mg/kg/day and initiated after surgery. Follow-up included a neurobehavioral assessment (locomotor activity, anxiety, working memory, special reference memory, visiospatial memory), imaging (tesla MRI 7, positron emission tomography), and immunohistochemistry at different time from 1,5 months to 12 months post-surgery.An initial WT mice cohort assessed at 6 weeks post-surgery demonstrated an impact of CMH on anxiety, spatial reference and visuospatial memory. An improvement in cognition performances was depicted under atorvastatin indicating this CMH-model is sensitive to pharmacological modulation.A longitudinal follow-up on WT and APP groups was performed assessing cognitive performances at 1.5, 3, 6, 9 and 12 months post-surgery. In WT mice, the CMH group showed a decreased level of anxiety and an impaired spatial reference memory at 1.5 months. Cognitive impairment was also found at 9 and 12 months in this group. This study did not allow to conclude in a precipitating or aggravating effect of the CMH in APP mice. The treatment by atorvastatin seemed to have a positive effect on cognition in both WT and APP mice. A decreased volume of ipsilateral hippocampus was observed in all APP and WT groups at 12 months. No difference in metabolism of brain structures was found.It is hypothesized that either the presence of CMB or the cerebrovascular damages underlying their occurrence may cause cognitive impairment. This study proved that isolated CMH can affect cognitive functions in WT mice, regardless of any underlying vascular pathology. It is likely that the burden of neurodegenerative lesions exceeds the cognitive impact of the CMH in APP mice. Atorvastatin seems to have a neuroprotective effect.
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Sandrine Bergeron. Microhémorragies cérébrales et cognition : impact fonctionnel à court, moyen et long termes dans un modèle murin. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2018. Français. ⟨NNT : 2018LIL2S048⟩. ⟨tel-02919173⟩

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