title: The Swedish APP mutation alters the effect of genetically reduced BACE1 expression on the APP processing.
abstract: Inhibition of β-secretase (BACE1) is a key therapeutic approach in Alzheimer's disease (AD), as BACE1 initiates amyloid-β (Aβ) cleavage from the β-amyloid precursor protein (APP). As Aβ reductions in mice lacking one BACE1 allele diverged considerably between studies we investigated the effect of BACE1 knock-out in more detail. With both BACE1 alleles the Swedish mutation (APP23 mice) increased APP processing and shifted it towards the β-secretase pathway as compared with non-mutated APP expressed at a similar level (APP51/16 mice). This effect was much smaller then observed in cell culture. An about 50% decrease in BACE1 enzyme activity resulted in a sub-proportional Aβ reduction with the Swedish mutation (-20%) and even less for non-mutated APP (-16%). In wild-type mice, the Aβ reduction may be even further diminished. Other metabolites of the β-secretase pathway decreased accordingly while the alternative α-secretase pathway increased. Complete BACE1 deletion strongly enhanced these changes. The remaining Aβ signal also described by others can be explained by assay cross-reactivity with other APP metabolites supporting BACE1 as the major β-secretase. Our data indicate that BACE1 is in excess over APP at the cleavage site(s). Alterations in APP expression or substrate properties, therefore, quantitatively change its cleavage and Aβ generation.
authors.affiliation: Neuroscience Discovery, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rabe
authors.forename: Julia
authors.initials: J
authors.lastname: Reichwald
authors.forename: Domenico
authors.initials: D
authors.lastname: Ammaturo
authors.forename: Bart
authors.initials: B
authors.lastname: de Strooper
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics*; D015153:Blotting, Western; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D012727:Sex Characteristics
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse