Generation of Alzheimer Disease-associated Amyloid β42/43 Peptide by γ-Secretase Can Be Inhibited Directly by Modulation of Membrane Thickness

Pathogenic generation of amyloid beta-peptide (A beta) by sequential cleavage of beta-amyloid precursor protein (APP) by beta- and gamma-secretases is widely believed to causally underlie Alzheimer disease (AD). beta-Secretase initially cleaves APP thereby generating a membrane-bound APP C-terminal fragment, from which gamma-secretase subsequently liberates 37-43-amino acid long A beta species. Although the latter cleavages are intramembranous and although lipid alterations have been implicated in AD, little is known of how the gamma-secretase-mediated release of the various A beta species, in particular that of the pathogenic longer variants A beta(42) and A beta(43), is affected by the lipid environment. Using a cell-free system, we have directly and systematically investigated the activity of gamma-secretase reconstituted in defined model membranes of different thicknesses. We found that bilayer thickness is a critical parameter affecting both total activity as well as cleavage specificity of gamma-secretase. Whereas the generation of the pathogenic A beta(42/43) species was markedly attenuated in thick membranes, that of the major and rather benign A beta(40) species was enhanced. Moreover, the increased production of A beta(42/43) by familial AD mutants of presenilin 1, the catalytic subunit of gamma-secretase, could be substantially lowered in thick membranes. Our data demonstrate an effective modulation of gamma-secretase activity by membrane thickness, which may provide an approach to lower the generation of the pathogenic A beta(42/43) species.