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

Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid beta-peptide (A beta) 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 A beta cascade. Exogenous A beta 42 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 A beta 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 A beta-induced upregulation of SPPL2b may enhance A beta production in a vicious cycle, further aggravating A beta pathology. Therefore, SPPL2b emerges as a potential anti-A beta drug target.