BJRP 011004

Super-resolution imaging of dendritic spine alterations induced by soluble oligomers of the betaamyloid peptide


Alzheimer’s disease (AD) is a devastating disorder for which there is currently neither an available cure nor an effective treatment. A prominent feature of the pathology of AD is that soluble oligomers of the beta-amyloid peptide (also known as ADDLs) attack dendritic spines, where most excitatory synapses are located. In spite of much scientific effort during the last decade, progress in understanding and treating AD has been hampered by lack of detailed information on the mechanisms of attack of synapses by ADDLs. Specifically, where and to what protein receptors do ADDLs bind, and what are the mechanisms for subsequent spine remodeling and loss. To address these questions, we will use a novel microscopy technique, photoactivated localization microscopy (PALM), which will allow us to obtain molecular-scale information about the dynamics and topography of ADDL binding to dendritic spines. In addition, we will perform sptPALM imaging on live-neurons that have been transfected to express a photoactivatable-labeled actin. From these experiments, we expect to learn more about the role of actin filament dynamics in spine morphological changes and eventual spine loss, two key phenotypes observed in AD patients.