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- Title
The Swedish APP mutation alters the effect of genetically reduced BACE1 expression on the APP processing.
- Authors
Rabe, Sabine; Reichwald, Julia; Ammaturo, Domenico; de Strooper, Bart; Saftig, Paul; Neumann, Ulf; Staufenbiel, Matthias
- Abstract
J. Neurochem. (2011) 119, 231-239. 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.
- Subjects
ALZHEIMER'S disease treatment; AMYLOID beta-protein precursor; GENETIC mutation; CELL culture; METABOLITES; LABORATORY mice
- Publication
Journal of Neurochemistry, 2011, Vol 119, Issue 1, p231
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2011.07412.x