Hyperphosphorylated tau has long been proposed as the key molecule disrupting 
normal neuronal microtubule dynamics and leading to neurofibrillary degeneration 
in Alzheimer disease. Here we provide a direct evidence of hyperphosphorylated 
tau-induced disruption of microtubule network. Using Nocodozole-treated and 
detergent-extracted cells, we created a neuronal environment in mouse embryonic 
fibroblasts, 3T3 cells, by replacing their cytoplasm with adult rat brain 
cytosol. By recreating neuronal microtubule network in these cells, we were able 
to follow the effects of hyperphosphorylated tau on microtubule dynamics in real 
time. Whereas recombinant human brain tau promoted assembly and bundling of 
microtubules, abnormally hyperphosphorylated tau isolated from Alzheimer disease 
brain cytosol (AD P-tau) inhibited the assembly and disrupted preformed 
microtubule network by sequestering normal brain tau and MAP2. This breakdown of 
the microtubule network was reversed by treatment of the extracted cells with 
protein phosphatase-2A. This study, for the first time, provides direct 
mechanistic insights into the molecular basis of both axonal and dendritic 
neurodegeneration seen in Alzheimer disease.