Amyloid-beta peptide (A beta) is believed to play a central role in the pathogenesis of Alzheimer's disease. In view of the side effects associated with inhibiting the secretases that produce A beta, new molecular targets are required to provide alternative therapeutic options. We used RNA interference (RNAi) to systematically screen the Drosophila genome to identify genes that modulate A beta production upon knockdown. RNAi of 41 genes in Drosophila cells significantly lowered A beta without affecting general secretion or viability. After the gamma-secretase complex components, the most potent effect was observed for platelet activating factor acetylhydrolase alpha (Paf-AH alpha), and, in mammalian cells, the effect was replicated for its ortholog PAFAH1B2. Knockdown of PAFAH1B2 strongly reduced A beta secretion from human cells, and this effect was confirmed in primary cells derived from PAFAH1B2 knock-out mice. Reduced A beta production was not attributable to altered beta-amyloid precursor protein (APP) ectodomain shedding but was a result of an enhanced degradation of APP C-terminal fragments (CTFs) in the absence of PAFAH1B2 but not its close homolog PAFAH1B3. Enhanced degradation of APP CTFs was selective because no such effects were obtained for Notch or E-/N-cadherin. Thus, we have identified an important protein that can selectively modify A beta generation via a novel mechanism, namely enhanced degradation of its immediate precursor. In view of the absence of a neurological phenotype in PAFAH1B2 knock-out mice, targeted downregulation of PAFAH1B2 may be a promising new strategy for lowering A beta.
Type of Publication:
Journal article published