Model depicting the dual role of p23 in APP trafficking and processing. Our results suggest that p23 has dual roles in the negative regulation of APP metabolism. First, the function of p23/p24 family proteins in early secretory trafficking of proteins at the ER-Golgi boundary influences APP biogenesis in a manner that stabilizes nascent APP, as well as enhances APP maturation and steady-state accumulation at the cell surface. Second, p23 can modulate Aβ production by influencing the proteolysis of APP CTF by modulation of γ-secretase. Cells transfected with p23 siRNA secrete increased levels of Aβ. Moreover, absence of p23 expression also results in increased Aβ generated by proteolysis of recombinant APP CTF substrate in cell free assays, providing strong support for the notion that this latter function occurs independent of vesicular trafficking.