Alterations in phosphatidylethanolamine levels affect the generation of Aß

Several studies suggest that the generation of A beta is highly dependent on the levels of cholesterol within membranes detergent-resistant microdomains (DRM). Indeed, the beta-amyloid precursor protein (APP) cleaving machinery, namely beta- and -secretases, has been shown to be present in DRM and its activity depends on membrane cholesterol levels. Counterintuitive to the localization of the cleavage machinery, the substrate, APP, localizes to membranes detergent-soluble microdomains enriched in phospholipids (PL), indicating that A beta generation is highly dependent on the capacity of enzyme and substrate to diffuse along the lateral plane of the membrane and therefore on the internal equilibrium of the different lipids of DRM and non-DRM domains. Here, we studied to which extent changes in the content of a main non-DRM lipid might affect the proteolytic processing of APP. As phosphatidylethanolamine (PE) accounts for the majority of PL, we focused on its impact on the regulation of APP proteolysis. In mammalian cells, siRNA-mediated knock-down of PE synthesis resulted in decreased A beta owing to a dual effect: promoted a-secretase cleavage and decreased -secretase processing of APP. In vivo, in Drosophila melanogaster, genetic reduction in PL synthesis results in decreased -secretase-dependent cleavage of APP. These results suggest that modulation of the membrane-soluble domains could be a valuable alternative to reduce excessive A beta generation.