Negative regulation of gamma-secretase mediated beta-amyloid production in Alzheimer's disease

gamma-Secretase is an aspartyl protease that cleaves multiple substrates within their transmembrane domains. gamma-Secretase processes APP to generate beta-amyloid (Abeta) peptides associated with Alzheimer's disease (AD). Here, we show that APP possesses an inhibitory domain that negatively modulates gamma-secretase activity. Furthermore, we have demonstrated that this inhibitory domain regulates gamma-secretase activity by binding to an allosteric site within gamma-secretase. Alteration of this inhibitory domain by deletion or mutation, as is seen with Flemish mutation, reduces its inhibitory potency and promotes Abeta production. Importantly, a peptide derived from this inhibitory domain exhibits selective inhibition of gamma-secretase activity for Abeta production over Notch1 processing. Therefore, this mode of regulation represents an unprecedented mechanism for modulating gamma-secretase and may provide a molecular basis for the pathogenesis of AD as well as a novel target for therapeutic development. This specialized mode of autoinhibition could serve as a common strategy in the regulation of proteases and other enzymes.;Processing of the amyloid precursor protein (APP) by beta- and gamma-secretases generates pathogenic beta-amyloid (Abeta) peptides associated with Alzheimer's disease (AD), whereas cleavage of APP by alpha-secretases precludes Abeta formation. Little is known about the role of alpha-secretase cleavage in gamma-secretase regulation. In another line of my work, we show that alpha-secretase cleaved APP C-terminal product (alpha-CTF) is a poor substrate and functions as an inhibitor of gamma-secretase. Moreover, we demonstrate that an inhibitory domain within alphaCTF, bisected by the alpha-secretase cleavage site, mainly contributes to this negative regulation and deleting or masking this domain turns alphaCTF to a better substrate of gamma-secretase. Inhibition of gamma-secretase activity by alphaCTF is witnessed in both in vitro and cellular systems. In summary, the present studies uncover a novel function of alpha-secretase that is opposite to beta-secretase cleavage in the regulation of gamma-secretase activity. alpha-Secretase cleavage negatively regulates gamma-secretase activity for APP processing. This work highlights fascinating twists in the link between gamma-secretrase and alpha-secretase cleavages for APP processing and reveals an unprecedented regulatory mechanism of gamma-secretase activity that could be key to our understanding of the diagnosis of and progression of AD.