“Complex Relationships between Substrate Sequence and Sensitivity to Alterations in gamma-Secretase Processivity Induced by gamma-Secretase Modulators”
Jung JI, Ran Y, Cruz PE, Rosario AM, Ladd TB, Kukar TL, Koo EH, Felsenstein KM, Golde TE. Biochemistry 2014.
γ-Secretase catalyzes the final cleavage of the amyloid precursor protein (APP) resulting in the production of amyloid-β (Aβ) peptides with different carboxyl termini. Presenilin (PSEN) and amyloid precursor protein (APP) mutations linked to early onset familial AD (FAD) modify the profile of Aβ isoforms generated, by altering both the initial γ-secretase cleavage site and subsequent processivity in a manner that leads to increased levels of the more amyloidogenic Aβ42 and in some circumstances Aβ43. Compounds referred to as γ-secretase modulators (GSMs) and inverse GSMs (iGSMs) can decrease or increase levels of Aβ42, respectively. As GSMs lower production of pathogenic forms of long Aβ isoforms, they are of great interest as potential AD therapeutics. The factors that regulate GSM modulation are not fully understood; however, there is a growing body of evidence that supports the hypothesis that GSM activity is influenced by the amino acid sequence of the γ-secretase substrate. We have evaluated whether mutations near the luminal border of the transmembrane domain (TMD) of APP alter the ability of both acidic, NSAID-derived carboxylate, and non-acidic, phenylimidazole-derived classes of GSMs and iGSMs to modulate γ-secretase cleavage. Our data show that point mutations can dramatically reduce sensitivity to modulation of cleavage by GSMs, but have less effect on iGSM activity. These studies support the concept that the effect of GSMs may be substrate selective; for APP it is dependent on amino acid sequence of the substrate near the junction of the extracellular domain and luminal segment of the TMD.