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Modélisation des phases précoces de la maladie d’Alzheimer par transfert de gènes

Mickaël Audrain 1
1 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
UP11 - Université Paris-Sud - Paris 11, MIRCEN - Service MIRCEN : DRF/JACOB, CNRS - Centre National de la Recherche Scientifique : UMR 9199
Abstract : Evaluation of biomarkers and new innovative therapies for Alzheimer's disease (AD) suffers from a misunderstanding of early phases and lack of appropriate animal models close to the human physiopathology. Most available rodent models reproduce hallmarks of AD such as amyloid plaques and neurofibrillary tangles in a few months, while it takes many years to be achieved in human. My PhD work consisted to develop a new modelling strategy of AD early phases without major overexpression of transgenes. To do so, we used gene transfer of human APPSL and PS1M146L using viral vectors injection in the hippocampus of 8 weeks old mice and rats. We characterized these models and showed peptides production, such as betaCTF and abeta42 from APP processing, similar to what is observed in AD patients hippocampi. We also highlighted a hyperphosphorylation of Tau followed by a synaptic failure characterized by a decrease of PSD-95 and GLT-1 levels and by an increase of the tonic current mediated by glutamate. These changes have been finally associated with behavioral deficits. My results suggest that many events appear well before the formation of amyloid plaques or tangles and lead to the disruption of the synapse and the early onset of behavioral defects. Thus, we now have relevant tools to understand the early stages of AD, which will allow us to test new drug compounds on these models with a wide therapeutic window and discover new early biomarkers in plasma and cerebrospinal fluid.
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Mickaël Audrain. Modélisation des phases précoces de la maladie d’Alzheimer par transfert de gènes. Neurosciences. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB010⟩. ⟨tel-01584477⟩

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