Validation fonctionnelle d'une nouvelle stratégie thérapeutique prévenant la dégénérescence et les troubles cognitifs associés dans des modèles murins de la Maladie d'Alzheimer

Abstract : No cure against Alzheimer's Disease (AD) exists yet, justifying the development of therapeutic strategies. Toxicity of soluble amyloid peptide is a key-player in early synaptic and cellular loss in AD. According to this hypothesis, we propose that preventing A peptide effects could prevent cogninitive decline in AD. Neurotrophic factors are good candidates to prevent cell death but require a targeted and continuous delivery. We used the cell encapsulation technology to produce graftable bioreactors that contain C2C12 cells secreting the Ciliary Neurotrophic factor (CNTF). Our goal was to realize the proof-of-concept that CNTF long term in situ delivery could prevent A-induced cognitive decline.Our studies prove that bioreactor-produced CNTF prevents A-induced cytotoxicity and apoptosis in vitro. Neuroprotection relies on PI3K and STAT3 activation. In vivo, bioreactor implantation in brain prevents cognitive impairment induced by A icv injection or delays their appearance in Tg2576 mice. In both of our preclinical model of AD, behavioral protection was associated with synapse maintenance in hippocampus.Therefore, in situ long term CNTF delivery is an efficient preventive therapeutic strategy against toxicity and A-linked cognitive disturbances. These results also suggest that encapsulated cells graft is a good way to deliver therapeutic molecules to the brain.
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Pierre Garcia. Validation fonctionnelle d'une nouvelle stratégie thérapeutique prévenant la dégénérescence et les troubles cognitifs associés dans des modèles murins de la Maladie d'Alzheimer. Médecine humaine et pathologie. Institut National Polytechnique de Lorraine, 2011. Français. ⟨NNT : 2011INPL084N⟩. ⟨tel-01749495⟩

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