We used a nontransgenic cellular tauopathy model in which individual giant 
neurons in the lamprey CNS (ABCs) overexpress human tau isoforms cell 
autonomously to characterize the still poorly understood consequences of 
disease-associated tau processing in situ. In this model, tau colocalizes with 
endogenous microtubules and is nontoxic when expressed at low levels, but is 
misprocessed by a toxicity-associated alternative pathway when expressed above 
levels that saturate dendritic microtubules, causing abnormally phosphorylated, 
vesicle-associated tau to accumulate in ABC distal dendrites. This causes 
localized microtubule loss and eventually dendritic degeneration, which is 
preceded by tau secretion to the extracellular space. This sequence is 
reiterated at successively more proximal dendritic locations over time, 
suggesting that tau-induced dendritic degeneration is driven by distal dendritic 
accumulation of hyperphosphorylated, vesicle-associated tau perpetuated by 
localized microtubule loss. The implications for the diagnosis and treatment of 
human disease are discussed.