Research ReportRegulation of tau proteolysis by phosphatases

One pathological hallmark of Alzheimer's disease is the accumulation of highly phosphorylated tau. Since tau phosphorylation inhibits its proteolysis, we examined the impact of endogenous phosphatase activities on tau proteolysis by homogenization of cultured cells and 3xTg-AD mouse brain followed by incubation with or without phosphatase inhibitors. Incubation without phosphatase inhibitors significantly increased tau immunoreactivity against antibody C3 (which reacts with tau truncated at D421), and increased the generation of tau breakdown products. These changes were augmented by lithium treatment and inhibited by constitutively active GSK3β. These findings underscore that tau proteolysis is regulated by a balance of kinase and phosphatase activities.

► Accumulation of highly phosphorylated tau accompanies Alzheimer neuropathology. ► Phosphorylation of tau has been shown to inhibit tau proteolysis. ► Endogenous phosphatases were manipulated by incubation±phosphatase inhibitors. These findings were compared with those of 3xTg-AD mice. ► Tau was degraded more rapidly and extensively without phosphatase inhibitors. ► Tau proteolysis is regulated by a balance of kinase and phosphatase activities.