Furin is an endogenous regulator of α-secretase associated APP processing

Constitutive and PKC-regulated α-secretase pathways have been reported to produce the secreted form of α-secretase-derived APP (sAPPα). Here, we examined putative role of furin in the regulation of α-secretase activity in vitro and in vivo. Overexpression of the prodomain of furin and infection with a furin-specific inhibitor significantly reduced the levels of sAPPα regardless of PKC activity, whereas total APP levels remained unchanged. Furin mRNA levels in the brains of AD patients and Tg2576 mice were significantly lower than those in controls, whereas ADAM10 and TACE mRNA levels were much alike between Tg2576 and littermate mice. Moreover, the injection of furin-adenovirus into Tg2576 mouse brains markedly increased α-secretase activity and reduced β-amyloid protein (Aβ) production in infected brain regions. Our results suggest that furin enhances α-secretase activity via the cleavage of ADAM10 and TACE, and that attenuated furin activity is connected to the production of Aβ.