The aim of this study is to better understand the role of Alzheimer's disease (AD) associated synaptic proteins in regulating synaptic structure and function in vivo. Using a newly developed membrane labeling technique to visualize neuronal structures, we will study the role of amyloid precursor protein (APP) and AP peptide in structural alterations of hippocampal synapses in transgenic mouse models of Alzheimer's disease. Preliminary studies suggest that dendrites in the vicinity of extracellular amyloid deposition show various abnormalities such as local sprouting, reduced dendritic spine density, and formation of varicosities. By using time-lapse recording and calcium imaging of fluorescently labeled dendrites in living hippocampal slices, we will examine whether and how amyloid deposition leads to morphological and functional disruption of synaptic connections. To better understand the mechanisms underlying synaptic dysfunction, serial electron microscopy will be used to examine ultrastructural changes and spatial relationships of axons, dendrites, and astrocytes in the vicinity of amyloid plaques. Lastly, as age-related synapse loss occurs gradually and long-term synaptic changes in the CNS are difficult to examine, we will study synaptic alterations in accessible submandibular ganglionic neurons in living mice expressing Yellow Fluorescent Protein (YFP) in preganglionic axons and synapses. We will be able to follow YFP-labeled synapses over an extended period of time to examine the long-term effect of age and AD associated proteins on synaptic loss in living mice. Because synapse loss plays an important role in the neuronal dysfunction associated with normal and pathological aging, a better understanding of how synapses change in Alzheimer's disease models is likely to be useful in developing new therapeutic approaches.
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