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.

Effects of TNFalpha-converting enzyme inhibition on amyloid beta production and APP processing in vitro and in vivo.

Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine that is elevated in Alzheimer's disease (AD) brains. Because TNFalpha is released from cell membranes by the TNFalpha-converting enzyme (TACE), inhibition of TACE has the potential to mitigate TNFalpha effects in AD brain. TACE also cleaves amyloid precursor protein (APP) and generates sAPPalpha, precluding the formation of potentially harmful amyloid beta (Abeta) peptides by beta-site APP cleaving enzymes (BACE).