Differential expression and modulation of presenilin-1 and presenilin-2 in neural cell lines

ABSTRACT Presenilin proteins, the catalytic components of the γ-secretase enzyme, play a key role in the pathogenesis of Alzheimer’s disease primarily by generating amyloid-β peptides. Although often grouped together, Presenilin-1 (PS1) and Presenilin-2 (PS2) are distinct proteins that contribute differently to γ-secretase activity. This study examines the differential expression of PS1 and PS2 in various neuroblastoma and microglial cell lines, along with compensatory responses following the ablation of one presenilin homologue. Using quantitative immunoblotting, we show that PS1 and PS2 expression levels vary significantly across cell types. Notably, the ablation of PS2 results in increased PS1 expression, particularly in microglial cells, highlighting the importance of PS2. Additionally, neuronal differentiation of two neuroblastoma lines, caused changes in protein expression levels resulting in similar expression profiles of PS1 and PS2, with PS2 levels being higher than PS1. Understanding PS expression profiles is crucial for distinguishing between PS1- and PS2-mediated γ-secretase activity and for developing γ-secretase-targeted therapeutics with improved selectivity.