Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease

Background: Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology arid progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. Methods: Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6 delta normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer's disease. Results: The newly identified inhibitors of the Rap1-Pde6 delta interaction counteract AD phenotypes, by reconfiguring Rapt signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or invivo. Thus, modulation of Rap1 by Pde6 delta accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders. Conclusion: Targeting the Pde6 delta-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer's disease

Faire connaître et valoriser sa bibliothèque

Comment faire connaître sa bibliothèque, rendre lisible son offre, valoriser ses évolutions ? Quels outils utiliser ? Quelles compétences intégrer ? Quelle organisation mettre en place ? Ces questions s'imposent aujourd'hui aux professionnels qui doivent améliorer la notoriété de leurs établissements et faire évoluer leur image. Dans ce livre, la relation avec les publics est placée au cœur du processus de communication, tant pour le contact en direct, les échanges en ligne, que pour le soin apporté aux espaces, à la signalétique, et à la conception de documents. Construire un plan de communication, mener une campagne d'affichage, réinventer un guide du lecteur, reformuler le règlement intérieur, créer un avatar ou partir à la conquête d'un public spécifique sont autant d'actions qui demandent à la fois de bâtir une stratégie d'ensemble et de maîtriser des savoirs pratiques et concrets. Pour chacune des réalisations évoquées, un mode opératoire précis indique la méthode et les étapes à prendre en compte. Coordonné par Jean-Marc Vidal, conservateur à la bibliothèque municipale de Grenoble, cet ouvrage collectif, qui réunit bibliothécaires, graphiste, responsable de communication, sociologue, rend compte d'expériences multiples menées dans des bibliothèques publiques et universitaires. La communication avec les publics apparaît ainsi comme l'un des éléments révélateurs des transformations des bibliothèques

Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer's disease

BACKGROUND: Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. METHODS: Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6δ normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer's disease. RESULTS: The newly identified inhibitors of the Rap1-Pde6δ interaction counteract AD phenotypes, by reconfiguring Rap1 signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or in-vivo. Thus, modulation of Rap1 by Pde6δ accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders. CONCLUSION: Targeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer's disease