Analysis of adaptations of cytoskeleton, dendritic spines and synaptic plasticity in relation to physiological and pathological phosphorylation of protein tau in vivo.

Firstly, we will analyse qualitatively and quantitatively the impact of separate and combined amyloid pathology and tau-opathy on dendritic spines in the hippocampus of single and bigenic transgenic mice that express mutant APP, mutant Tau and GSK-3. This analysis will already start in 2007 and will continue in the project as it will involve analysis of mice even at old ages (2-4, 4-6, 6-8, 10-12, 15-18 months). We will define the progression and particularly pinpoint the earliest age at which problems with spine density and synaptic density are expressed. We thereby will gain insight into the start and progression of the disease process mediated by amyloid and tau, separately and combined as in AD. Secondly, we will analyse in depth these transgenic models at the most relevant age to define in detail the actual defects in hippocampal spines and synapses, correlated with (i) biochemical analysis; (ii) immuno-histochemical and -cytochemical analysis and (iii) cognitive and electrophysiological analysis. We thereby will gain insight in the condition equivalent to MCI and its progression into AD.Thirdly, we will analyse and define molecular actions and relations in vivo and in neuronal cultures by analysing the most crucial players involved in known or suspected signaling pathways. The "candidate" approach will comprise painstaking biochemical and immuno-cytochemical analysis of components or their modifications, mainly phosphorylation of pathways like Wnt, Eph, insulin, ... involving on GSK-3, cdk5, mTOR, among others. We will analyse modifications of microtubuli and of the actin-filament network to define relations to each other, to synapses, especially pre-synaptic vesicles and post-synaptic density. We thereby will gain insight into molecular defects inflicted by amyloid peptides and hyper-phosphorylated tau.

Keywords:in vivo, Alzheimer's Disease, Dendritic spines, Synaptic plasticity, Tau

Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences, Genetics, Systems biology, Molecular and cell biology, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing