Abstract: Objective To explore whether Nicastrin undergoes ubiquitination before proteasomal degradation, as well as the relationship between Nicastrin protein level and Aβ generation. Methods Cell fractionation, western blot, immunoprecipitation as well as ELISA were used to check the expression of NCT and Aβ level. Results NCT distributes primarily in ER and Golgi apparatus, less NCT in lysosome, and increased NCT accumulates in the ER and Golgi apparatus after proteasomal inhibition. NCT and ubiquitin colocalize and interact with each other in cells. The degradation of NCT was not affected by PS. Overexpression of NCT by transient NCT plasmid transfection or inhibition of NCT proteasomal degradation can decrease substrate of　γ-secretase, C99 and C83, and increase production of γ-secretase, Aβ40 and Aβ42（p<0.01）. Conclusion The degradation of NCT is by the way of the ubiquitin-proteasome pathway. The expression of NCT is increased following proteasomal inhibition, and over-expression of NCT can facilitate APP processing and Aβ generation.