Abnormally hyperphosphorylated tau is the major protein constituent of 
neurofibrillary tangles (NFTs) in the brain of Alzheimer disease (AD) patients. 
Cell cycle reactivation is considered an important neuropathological feature of 
AD, and re-expression and activation of cell cycle regulators are known to occur 
in neurons containing NFTs. The aim of the present study was to investigate cell 
cycle reactivation during tau hyperphosphorylation in primary hippocampal 
neurons. We used forskolin, a specific activator of PKA, to induce tau 
hyperphosphorylation in cultured primary hippocampal neurons, and then measured 
levels of cyclin D1 and cyclin B1. We found that forskolin induced 
hyperphosphorylation of tau at Ser214, Ser396, and Ser202/Thr205 sites, 
attaining peak levels at 6, 12, and 12 h, respectively, while returning to 
normal levels at 24 h. Forskolin also induced a sustained cAMP elevation and PKA 
activation, which peaked at 6 h, in association with activation and 
overexpression of protein phosphatase-2A (PP-2A) at 24 h. The tau 
hyperphosphorylation was accompanied by increases in cyclin D1 and cyclin B1 
levels; immunostaining showed overlapping distribution of hyperphosphorylated 
tau and cyclin D1 and cyclin B1 in primary hippocampal neurons. Forskolin 
induced hyperphosphorylation of tau and increased cyclin D1 and cyclin B1 
protein levels in HEK293/tau441 cells, but not in the HEK293/vector cells, 
whereas the PKA inhibitor H89 inhibited the effects of forskolin on tau 
hyperphosphorylation and cyclin D1 and cyclin B1 protein levels. These findings 
suggest that forskolin induces tau hyperphosphorylation, which is itself 
necessary for the subsequent increases of cyclin D1 and cyclin B1 levels.