AbstractThe gamma‐secretase is a multiprotein complex that cleaves many type‐I membrane proteins, such as the Notch receptor and the amyloid precursor protein. Nicastrin (NCT) is an essential component of the multimeric gamma‐secretase complex and functions as a receptor for gamma‐secretase substrates. In this study, we found that Akt1 markedly regulated the protein stability of NCT. Importantly, the kinase activity of Akt1 was essential for the inhibition of gamma‐secretase activity through degradation of NCT. Notably, the protein level of endogenous NCT was higher in shAkt1‐expressing cells than in shCon‐expressing cells. Akt1 physically interacted with NCT and mediated its degradation through proteasomal and lysosomal pathways. We also found that Akt1 phosphorylates NCT at Ser437, resulting in a significant reduction in NCT protein stability. Importantly, a phospho‐deficient mutation in NCT at Ser437 stabilized its protein levels. Collectively, our results reveal that Akt1 functions as a negative regulator of the gamma‐secretase activity through phosphorylation and degradation of NCT. image Generation of the amyloid peptide (A‐beta) and the amyloid precursor protein (APP) intracellular domain (AICD) can happen by sequential proteolysis of APP by beta and gamma‐secretase. The gamma‐secretase complex consists of four essential proteins: presenilin (PS1 or PS2), presenilin enhancer 2 (PEN‐2), anterior pharynx‐defective 1 (APH‐1), and the Nicastrin (NCT). NCT can interact and be phosphorylated by Akt1, and phosphorylated NCT promotes its proteasomal and lysosomal degradation. As a result, Akt1 plays role in reducing gamma‐secretase activity through phosphorylation‐dependent regulation of NCT protein degradation.