An alternative spliced mouse presenilin-2 mRNA encodes a novel γ-secretase inhibitor

Abstract

The γ-secretase, composed of presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin (NCT), anterior pharynx-defective phenotype 1 (APH-1), and PEN-2, is critical for the development of Alzheimer’s disease (AD). PSs are autoproteolytically cleaved, producing an N-terminal fragment (NTF) and a hydrophilic loop domain-containing C-terminal fragment. However, the role of the loop domain in the γ-secretase complex assembly remains unknown. Here, we report a novel PS2 isoform generated by alternative splicing, named PS2β, which is composed of an NTF with a hydrophilic loop domain. PS2β disturbed the interaction between NCT and APH-1, resulting in the inhibition of amyloid-β production. We concluded that PS2β may inhibit γ-secretase activity by affecting the γ-secretase complex assembly. Structured summary MINT- 7025654: APH1 (uniprotkb: Q96BI3) physically interacts (MI: 0218) with PEN2 (uniprotkb: Q9NZ42), PS2 beta (uniprotkb: Q61144-2) and PS1 (uniprotkb: P49769) by anti tag coimmunoprecipitation (MI: 0007) MINT- 7025631: APH1 (uniprotkb: Q96BI3) physically interacts (MI: 0218) with NCT (uniprotkb: Q92542), PEN2 (uniprotkb: Q9NZ42) and PS1 (uniprotkb: P49769) by anti tag coimmunoprecipitation (MI: 0007)