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

Amyloid-beta (Abeta) 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 Abeta 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 Abeta secretion. Previous studies have demonstrated that insulin or IGF-1 stimulation can increase Abeta 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 multiple cell lines. Myr-Akt overexpression also resulted in increased APP protein stability. Since the insulin/IGF-1 signaling pathway is tightly regulated by feedback inhibition pathways, we hypothesized that myr-Akt overexpression may be inducing feedback inhibition of PI3K, resulting in impaired APP trafficking. In support of this hypothesis, myr-Akt acted at a known node of PI3K inhibition and decreased insulin receptor substrate 1 (IRS1) protein levels. Our studies provide further support for PI3K as a modulator of APP trafficking and demonstrate that overactivation of the insulin/IGF-1 signaling pathway may result in feedback inhibition of PI3K through IRS1 and reduce APP trafficking and Abeta secretion.