Imaging changes in neurodegenerative disease

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• Tara L Spires-Jones Massachusetts General Hospital, Harvard Medical School, Charlestown, MA USA.
• Wednesday 01 April 2009, 11:00-11:45
• Cripps Court, Magdalene College.

If you have a question about this talk, please contact Anna Di Pietro.

Imaging transgenic models of neurodegenerative diseases provides insight into disease pathology, progression, and feasibility of treatments for these devastating conditions. Alzheimer’s disease is the most common cause of dementia in the elderly, and is becoming a pressing public health issue in the first world as our population ages. During the course of Alzheimer’s disease, the brain develops extracellular senile plaques composed largely of aggregated amyloid beta peptide, intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, and synapses and neurons are progressively lost leading to neural systems failure. We use imaging techniques to study the relationship of pathology to synapse and neuronal loss and whether these degenerative pathways can be effectively stopped or reversed. Multiphoton imaging of transgenic models allows observation of the development of pathology and degeneration of synapses and neurons over time in the living brain. In mouse models overexpressing 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 swellings, and dendritic spine collapse. Treatment of these mice with immunotherapy has beneficial effects on synaptic plasticity and neurite anatomy, thus restoring synaptic circuitry. In mice overexpressing mutant human tau, we observe that tangles also form over the course of days, and that neurofibrillary tangle formation is preceded by neuronal caspase activation. Neurites also degenerate over hours in tau transgenic mice in a caspase-associated manner. Suppression of the tau transgene causes recovery of memory and reduces caspase activation, tangle formation, and neuronal loss. While in vivo imaging is a powerful tool for analysis of kinetics of degenerative processes, advanced imaging techniques can also be used post-mortem in fixed tissue samples of both animal models and patients to study synaptic and neuronal alterations and protein interactions and confirmations in detail. For example, we used the new array tomography technique to determine that oligomeric amyloid beta associates with synapses and correlates with plaque-associated synapse loss. We also developed new techniques for fluorescence lifetime imaging to show conformational changes of the tau protein during development of neurofibrillary pathology and differences in Apolipoprotein E4 interaction with amyloid beta compared to Apolipoprotein E3. Together, imaging studies of plaque and tangle bearing models have contributed to a hypothesis of how pathology develops and leads to synapse and neuronal loss in Alzheimer’s disease and indicate places in the degenerative pathways to intervene to prevent cognitive decline.

This talk is part of the Spring School 2009 - "Regeneration and Plasticity of Neural Circuits" series.

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