γ-Secretase modulators exhibit selectivity for modulation of APP cleavage but inverse γ-secretase modulators do not.

ABSTRACT:

Background

γ-Secretase is a multiprotein protease that cleaves amyloid protein precursor (APP) and other type I transmembrane proteins. It has two catalytic subunits, presenilins 1 and 2 (PS1 and 2). In our previous report, we observed subtle differences in PS1- and PS2-mediated cleavages of select substrates and slightly different potencies of PS1 versus PS2 inhibition for select γ-secretase inhibitors (GSIs) on various substrates. In this study, we investigated whether γ-secretase modulators (GSMs) and inverse γ-secretase modulators (iGSMs) modulate γ-secretase processivity using multiple different substrates. We next used HEK 293T cell lines in which PSEN1 or PSEN2 was selectively knocked out to investigate processivity and response to GSMs and iGSMs.

Methods

For cell-fre

SUBMITTER: Lessard CB 

PROVIDER: S-EPMC7236921 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature