Résumés disponibles (91) :

DUJARDIN Simon (INSERM U1172 éq. 01 - Morvane COLIN)
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@mail :  simon.dujardin@inserm.fr      tél. :  0320298856

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Titre de la communication :
Trans-synaptic transfer of human WT Tau, involvement of vesicular pathways
Auteurs (et leurs adresses) de la communication :
Dujardin Simon, Caillierez Raphaëlle, Zommer Nadège, Bégard Séverine, Delattre Lucie, Loyens Anne, Aurégan Gwennaëlle, Galas Marie-Christine, Deglon Nicole, Brouillet Emmanuel, Hantraye Philippe, Buée Luc and Colin Morvane
Résumé de la communication :
Abundant and abnormal accumulation of Tau, a hyperphosphorylated microtubule-associated protein, is the main pathological feature for a heterogeneous group of neurodegenerative disorders, so-called tauopathies. For many years this neurodegeneration was incriminated to the aggregation of an intracellular form of Tau in a specific process: neurofibrillary degeneration (NFD). Different groups, including ours now showed that NFD is able to spread in a hierarchical pattern during pathology along existing neural networks but how the propagation of NFD occurs is still unclear. The aim of the present study was to clarify the behaviour of Tau proteins during this propagation process. To address this question we took advantage of a new lentiviral rat model of tauopathy recently developed in our team (Caillierez et al., 2013). We specifically designed new lentiviral vectors (LVs) encoding the full length 4R wild-type (WT) human Tau (2+3-10+ / hTau46WT) tagged with a V5 epitope to discriminate murine endogenous Tau protein from the human overexpressed one. These LVs were stereotactically injected into the ventral hippocampus, area early affected in Alzheimer Disease and well known for its connections to distant brain regions such as prelimbic cortex and olfactory areas. We demonstrated for the first time in vivo, that WT-Tau proteins are able to transfer from the hippocampal formation to several trans-synaptically connected regions invading with time distant brain regions. We also showed that once transported into the secondary connected-neurons, V5-tagged WT Tau proteins drive Tau hyperphosphorylation by themselves but also probably by seeding the pathology. However, mechanisms leading to cell-to-cell transfer of a cytosolic protein are still yet unknown. In this context, we investigated if Tau might be present into vesicles known to be implied in cell-to-cell communication. Vesicles from culture media of neuroblastoma cell lines and primary cultures of rat embryonic cortical neurons were purified in vitro by differential centrifugations. Biochemical assays and electron microscopy allowed us to visualize WT Tau proteins inside these vesicles. This study brings new direct evidences that WT Tau protein is cell-to-cell transferred at least thanks to vesicular systems driving the spreading of pathology throughout the brain during sporadic tauopathies.

Caillierez, C, Bégard, S, Lécolle, K, Deramecourt, V, Zommer, N, Dujardin, S, Loyens, A, Dufour, N, Aurégan, G, Winderickx, J, Hantraye, P, Déglon, N, Buée, L and Colin, M. Lentiviral Delivery of the Human Wild-type
Tau Protein Mediates a Slow and Progressive Neurodegenerative Tau Pathology in the Rat Brain. Molecular therapy, 2013

DUJARDIN Simon (INSERM U1172 éq. 01 - Morvane COLIN)