Paper

Signal Peptide Peptidase-Like 2b affects APP cleavage and exhibits a biphasic Aβ-mediated expression in Alzheimer′s disease

Andrade-Talavera, Yuniesky, Fisahn, André, Jiang, Richeng, Picciau, Federico, Zerial, Stefania, Nilsson, Per, Maccioni, Riccardo, Schröder, Bernd, Tambaro, Simone, Wagener, Annika, Lemoine, Laetitia, Mentrup, Torben, Fluhrer, Regina, Travisan, Caterina, Grassi, Caterina, Chen, Gefei

2022

Overview

Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. To identify new druggable pathways involved in the Aβ cascade we here investigated the AD pathophysiological role of the presenilin-like intramembrane protease signal peptide peptidase-like 2b (SPPL2b). Aβ42 induced a biphasic modulation of SPPL2b expression in human cell lines and ex vivo mouse brain slices. In addition, SPPL2b was elevated in AppNL-G-F knock-in AD mice as well as in human AD samples. Early high neuronal expression of SPPL2b was followed by a downregulation in late AD pathology in both AppNL-G-F mice and Braak stage V AD brains. Importantly, SPPL2b overexpression or its genetic deletion significantly increased or reduced APP cleavage and Aβ production, respectively. Thus, our results strongly support the involvement of SPPL2b in AD pathology. The early Aβ-induced SPPL2b upregulation may enhance Aβ production in a vicious cycle further aggravating the Aβ pathology suggesting SPPL2b as a potential anti-Aβ drug target. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press
• Subject: Alzheimer's disease / Brain slice preparation / Cell lines / Neurodegenerative diseases / Pathology / Peptides / Presenilin / Signal peptide peptidase / Therapeutic targets / β-Amyloid