Accumulation of hyperphosphorylated tau protein into neurofibrillary tangles (NFT) in Alzheimer disease and other tauopathies correlates with neuron loss and cognitive decline; but the relationship of NFT to neuron dysfunction and death in neurodegenerative diseases remains unclear. Recently, a regulatable transgenic mouse line was developed (rTg4510) that expresses human tau with the tauopathy-associated P301L mutation, which can be suppressed with doxycycline. These mice develop progressive behavioral deficits, neuron loss, and tangle formation that can be prevented by transgene suppression (SantaCruz et al., 2005, submitted; Orne et al, sfn 2005 poster). In this study cortical neurons of rTg4510 and control mice were infected with adeno-associated virus carrying the gene for enhanced green fluorescent protein and in vivo multiphoton microscopy was used to investigate neuron morphology and tangles in the living brain. We observe thioflavine S positive neurons similar to staining of NFT in human tauopathy...