Signal Peptide Peptidase-Like 2b affects APP cleavage and exhibits a biphasic Aβ-mediated expression in Alzheimer's disease.
Alzheimers disease (AD) is a multifactorial disorder driven by abnormal amyloid {beta}-peptide (A{beta}) levels. To identify new druggable pathways involved in the A{beta} cascade we here investigated the AD pathophysiological role of the presenilin-like intramembrane protease signal peptide peptidase-like 2b (SPPL2b). A{beta}42 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 A{beta} production, respectively. Thus, our results strongly support the involvement of SPPL2b in AD pathology. The early A{beta}-induced SPPL2b upregulation may enhance A{beta} production in a vicious cycle further aggravating the A{beta} pathology suggesting SPPL2b as a potential anti-A{beta} drug target.