Constitutively active Akt inhibits trafficking of amyloid precursor protein and amyloid precursor protein metabolites through feedback inhibition of phosphoinositide 3-kinase.

Amyloid-β (Aβ) peptides, generated through sequential proteolytic cleavage of amyloid precursor protein (APP), aggregate to form amyloid plaques in Alzheimer’s disease (AD). Understanding the regulation of Aβ generation and cellular secretion is critical to our understanding of AD pathophysiology. In the present study, we examined the role of the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway in regulating APP trafficking and Aβ secretion. Previous studies have demonstrated that insulin or IGF-1 stimulation can increase Aβ and APP secretion in a phosphoinositide 3-kinase (PI3K) dependent manner. To expand upon these studies and better understand the molecular targets responsible for alterations in APP secretion, we constitutively activated Akt, a downstream component of the insulin/IGF-1 signaling pathway. Counterintuitively, constitutively active Akt (myr-Akt) overexpression produced an opposite effect to insulin/IGF-1 stimulation and inhibited secretion of APP and APP metabolites in mult...