The regulation of presenilin-1 by nerve growth factor

Presenilin-1 (PS1) protein concentration is linked to neuronal development and to the pathogenesis of Alzheimer's disease, yet little is known about t he biological factors and mechanisms that control cellular levels of PS1 pr otein. As PS1 levels are highest in the developing brain, we tested whether neurotrophin-induced differentiation influences PS1 expression using neuro notypic pheochromocytoma (PC12) cells. Treatment of PC12 cells with nerve g rowth factor (NGF) caused similar to 60-75% increases in the steady-state l evels of endogenous PS1 N- and C-terminal fragments. PSI protein accumulati on was dose-responsive to NGF and required the presence of the TrkA NGF rec eptor tyrosine kinase. NGF also induced PS1 fragment accumulation in cultur ed exp[ants of rat dorsal root ganglia. Quantitative northern blot analysis using PC12 cultures indicated that NGF did not increase steady-state PS1 m RNA levels. However, pulse-chase experiments indicated that NGF slowed the degradation rate of endogenous PS1 fragments, increasing the half-life from t(1/2) @22.5 to @25.0 h. This increase in half-life was insufficient to ac count for the similar to 60-75% increase in PS1 fragment levels measured in NGF-treated cells. Thus, NGF may regulate PS1 protein concentration in NGF -responsive cells by a complex mechanism that increases PS1 fragment produc tion independent of holoprotein synthesis.