Novel γ-secretase modulators directly target presenilin
J Biol Chem. 2011 Oct 28;286(43):37181-6. Epub 2011 Sep 6.
|Type of Publication:||Journal Article|
γ-Secretase is essential for the generation of the neurotoxic 42 amino acid amyloid β-peptide (Aβ42). The aggregation-prone hydrophobic peptide, which is deposited in Alzheimer disease (AD) patient brain, is generated from a C-terminal fragment (CTF) of the β-amyloid precursor protein (APP) by an intramembrane cleavage of γ-secretase. Since Aβ42 is widely believed to trigger AD pathogenesis, γ-secretase is a key AD drug target. Unlike inhibitors of the enzyme, γ-secretase modulators (GSMs) selectively lower Aβ42 without interfering with the physiological function of γ-secretase. The molecular target(s) of GSMs and hence the mechanism of GSM action are not established. Here we demonstrate by using a biotinylated photocrosslinkable derivative of highly potent novel second-generation GSMs, that γ-secretase is a direct target of GSMs. The GSM-photoprobe specifically bound to the N-terminal fragment of presenilin (PS), the catalytic subunit of γ-secretase, but not to other γ-secretase subunits. Binding was differentially competed by GSMs of diverse structural classes indicating the existence of overlapping / multiple GSM binding sites or allosteric alteration of the photoprobe binding site. The APP CTF previously implicated as GSM binding site was not targeted by the compound. The identification of PS as molecular target of GSMs directly establishes allosteric modulation of enzyme activity as a mechanism of GSM action and may contribute to the development of therapeutically active GSMs for the treatment of AD.