A transitory activation of protein kinase-A induces a sustained tau hyperphosphorylation at multiple sites in N2a cells-imply a new mechanism in Alzheimer pathology

Overactivation of protein kinase in the end stage of Alzheimer's disease brain has not been established. The purpose of the present study was to explore the possible mechanism for protein kinases in leading to Alzheimer-like tau hyperphosphorylation. We found that incubation of N2a/tau441 with forskolin, a specific activator of cAMP-dependent protein kinase (PKA), induced an increased phosphorylation level of tau at both PKA and non-PKA sites in a dose- and time-dependent manner, and the hyperphosphorylation of tau was positively correlated with the elevation of PKA activity. When the cells were transitorily incubated with forskolin, a temporary activation of PKA with a sustained and almost equally graded tau hyperphosphorylation at some non-PKA sites was observed. In either case, the activity of glycogen synthase kinase-3 (GSK-3) was not changed. It is suggested that only transitory activation of PKA in early stage of Alzheimer disease may result in a sustained tau hyperphosphorylation at multiple sites, implying a new mechanism to Alzheimer-like tau hyperphosphorylation.