"Neuronal circuits in mammalian brain act predominantly via excitatory synapses on dendritic spines. Formation of new spines in adult brain constitutes the structural basis of neuronal plasticity. The underlying molecular mechanisms remain largely unknown but depend essentially on kinase-dependent signalling pathways. Final formation of synapses on spines depends on dynamic interactions of microtubuli and actin-filaments that are also controlled by kinases. Deterioration of these processes to different extents are thought to cause the cognitive decline in normal ageing as well in Alzheimer's disease (AD) and familial fronto-temporal dementia (FTD). Protein tau is a microtubule associated protein and GSK-3 kinases are proposed as the major tau-kinases in vivo. Their exact contributions remain to be functionally defined in vivo both in normal neuronal plasticity and in degeneration. We develop pre-clinical models for AD and FTD that have tauopathy in common as essential pathogenic component and will explore the GSK-3 kinases in vivo by manipulating their activity genetically, pharmacologically and biochemically. Inhibitors are wanted that are effective and specific and enter brain in vivo. This proposal engages in three activities: (i) elucidate physiological functions of GSK-3 kinases in synaptic plasticity in adult and ageing brain, and in degenerating brain; define fundamental neuron-specific functions of GSK-3 kinases in vivo in novel mouse models; define contributions of GSK-3 kinases to amyloid and to tau pathology, separately and combined in vivo in validated mouse models (ii) design novel inhibitors of GSK-3 kinases and alternative tools to inhibit GSK-3 activity in vivo (iii) test pharmacological and peptidometic inhibitors of GSK-3 in validated mouse models of neurodegeneration for their restorative potential; analyse their mode of action and their acute and chronic effects by multi-parametric analysis"