Suppression of γ‐secretase activity increases ganglioside levels at neuritic terminals of differentiated PC12

Abstract

Mutations in presenilin genes cause the dominant type of familial Alzheimer disease. Presenilin mutations have recently been argued to work as loss‐of‐function; however, their pathological significance remains obscure. In this study, we investigated whether presenilins are involved in the regulation of the distribution of neuronal membrane lipids by treatment of neuronally differentiated PC12 with DAPT, an inhibitor of presenilin‐dependent γ‐secretase. Levels of membrane lipids in neuritic terminals and neuronal somata were analyzed using electrospray ionization tandem mass spectrometry. Through DAPT treatment, whereas cholesterol level stayed unchanged, the levels of phosphatidylcholine and sulfatide increased in both neuritic terminals and neuronal somata. Remarkably, the levels of gangliosides increased in neuritic terminals but decreased in neuronal somata by DAPT treatment concomitant with similar alteration for sphingomyelin. Considering the previous findings that accumulation of gangliosides and sphingomyelin at neuritic terminals induces Aβ amyloid formation, these results suggest that a decrease in γ‐secretase activity affects membrane lipids environment as leading to facilitation of Aβ amyloid formation in the brain. This study was supported by a Grant‐in‐Aid for Research Activity start‐up and for Scientific Research (B) from the Japan Society for the Promotion of Science.