Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators.

ABSTRACT: γ-Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN-2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early-onset AD GSECs successively cut APP to generate amyloid-β (Aβ) peptides of various lengths. AD-causing mutations destabilize GSEC-APP/Aβ_n interactions and thus enhance the production of longer Aβs, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP/Aβ_n during the sequential proteolysis. Our studies reveal that a d

SUBMITTER: Petit D 

PROVIDER: S-EPMC6576158 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature