BEGIN:VCALENDAR VERSION:2.0 PRODID:-//Talks.cam//talks.cam.ac.uk// X-WR-CALNAME:Talks.cam BEGIN:VEVENT SUMMARY:Imaging changes in neurodegenerative disease - Tara L Spires-Jones Massachusetts General Hospital\, Harvard Medical School\, Charlestown\, MA USA. DTSTART:20090401T100000Z DTEND:20090401T104500Z UID:TALK17648@talks.cam.ac.uk CONTACT:Anna Di Pietro DESCRIPTION:Imaging transgenic models of neurodegenerative diseases provid es insight into disease pathology\, progression\, and feasibility of treat ments for these devastating conditions. Alzheimer’s disease is the mos t common cause of dementia in the elderly\, and is becoming a pressing pub lic health issue in the first world as our population ages. During the co urse of Alzheimer’s disease\, the brain develops extracellular senile pl aques composed largely of aggregated amyloid beta peptide\, intracellular neurofibrillary tangles containing hyperphosphorylated tau protein\, and s ynapses and neurons are progressively lost leading to neural systems failu re. We use imaging techniques to study the relationship of pathology to s ynapse and neuronal loss and whether these degenerative pathways can be ef fectively stopped or reversed. Multiphoton imaging of transgenic models a llows observation of the development of pathology and degeneration of syna pses and neurons over time in the living brain. In mouse models overexpre ssing Alzheimer’s-associated mutant amyloid precursor protein\, we have found that plaques develop very quickly (over days) and cause degenerative changes in surrounding neurites including curvature\, dystrophic swelling s\, and dendritic spine collapse. Treatment of these mice with immunother apy has beneficial effects on synaptic plasticity and neurite anatomy\, th us restoring synaptic circuitry. In mice overexpressing mutant human tau\ , we observe that tangles also form over the course of days\, and that neu rofibrillary tangle formation is preceded by neuronal caspase activation. Neurites also degenerate over hours in tau transgenic mice in a caspase-a ssociated manner. Suppression of the tau transgene causes recovery of mem ory and reduces caspase activation\, tangle formation\, and neuronal loss. While in vivo imaging is a powerful tool for analysis of kinetics of deg enerative processes\, advanced imaging techniques can also be used post-mo rtem in fixed tissue samples of both animal models and patients to study s ynaptic and neuronal alterations and protein interactions and confirmation s in detail. For example\, we used the new array tomography technique to determine that oligomeric amyloid beta associates with synapses and correl ates with plaque-associated synapse loss. We also developed new technique s for fluorescence lifetime imaging to show conformational changes of the tau protein during development of neurofibrillary pathology and difference s in Apolipoprotein E4 interaction with amyloid beta compared to Apolipopr otein E3. Together\, imaging studies of plaque and tangle bearing models have contributed to a hypothesis of how pathology develops and leads to sy napse and neuronal loss in Alzheimer’s disease and indicate places in th e degenerative pathways to intervene to prevent cognitive decline. LOCATION:Cripps Court\, Magdalene College END:VEVENT END:VCALENDAR