PDAPP; YFP double transgenic mice: a tool to study amyloid-beta associated changes in axonal, dendritic, and synaptic structures.

ABSTRACT

Neuritic plaques are one of the stereotypical hallmarks of Alzheimer's disease (AD) pathology. These structures are composed of extracellular accumulations of fibrillar forms of the amyloid-beta peptide (Abeta), a variety of other plaque-associated proteins, activated glial cells, and degenerating nerve processes. To study the neuritic toxicity of different structural forms of Abeta in the context of regional connectivity and the entire cell, we crossed PDAPP transgenic (Tg) mice, a model with AD-like pathology, to Tg mice that stably express yellow fluorescent protein (YFP) in a subset of neurons in the brain. In PDAPP; YFP double Tg mice, markedly enlarged YFP-labeled axonal and dendritic varicosities were associated with fibrillar Abeta deposits. These varicosities were absent in areas where there were nonfibrillar Abeta deposits. Interestingly, YFP-labeled varicosities revealed changes that corresponded with changes seen with electron microscopy and the de Olmos silver staining technique. Other silver staining methods and immunohistochemical localization of phosphorylated neurofilaments or phosphorylated tau were unable to detect the majority of these dystrophic neurites. Some but not all synaptic vesicle markers accumulated abnormally in YFP-labeled varicosities associated with neuritic plaques. In addition to the characterization of the effects of Abeta on axonal and dendritic structure, YFP-labeled neurons in Tg mice should prove to be a valuable tool to interpret the localization patterns of other markers and for future studies examining the dynamics of axons and dendrites in a variety of disease conditions in living tissue both in vitro and in vivo.