Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer's disease

• Published in: Progress in neurobiology 2024-04, Vol.235, p.102585-102585, Article 102585
• Main Authors: Maccioni, Riccardo, Travisan, Caterina, Badman, Jack, Zerial, Stefania, Wagener, Annika, Andrade-Talavera, Yuniesky, Picciau, Federico, Grassi, Caterina, Chen, Gefei, Lemoine, Laetitia, Fisahn, André, Jiang, Richeng, Fluhrer, Regina, Mentrup, Torben, Schröder, Bernd, Nilsson, Per, Tambaro, Simone
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid β; AppNL-G-F knock-in mice; BRI2; Medicin och hälsovetenskap; Microglia; SPPL2b
• ISSN: 0301-0082; 1873-5118; 1873-5118
• DOI: 10.1016/j.pneurobio.2024.102585

Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aβ cascade. Exogenous Aβ42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of AppNL-G-F knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in AppNL-G-F mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aβ production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aβ-induced upregulation of SPPL2b may enhance Aβ production in a vicious cycle, further aggravating Aβ pathology. Therefore, SPPL2b emerges as a potential anti-Aβ drug target. •Aβ42 modulates the expression of the presenilin-like intramembrane SPPL2b peptidase.•SPPL2b affects BRI2, APP cleavage, and Aβ production.•SPPL2b colocalizes with APP and is expressed in the neuronal spines.•Genetic deletion of SPPL2b in mice reduced APP cleavage and Aβ production.•Early high up-regulation of SPPL2b is followed by a down-regulation in AD AppNL-G-F mice.