| First Author | Rabe S | Year | 2011 |
| Journal | J Neurochem | Volume | 119 |
| Issue | 1 | Pages | 231-9 |
| PubMed ID | 21812781 | Mgi Jnum | J:176601 |
| Mgi Id | MGI:5292289 | Doi | 10.1111/j.1471-4159.2011.07412.x |
| Citation | Rabe S, et al. (2011) The Swedish APP mutation alters the effect of genetically reduced BACE1 expression on the APP processing. J Neurochem 119(1):231-9 |
| abstractText | Inhibition of beta-secretase (BACE1) is a key therapeutic approach in Alzheimer's disease (AD), as BACE1 initiates amyloid-beta (Abeta) cleavage from the beta-amyloid precursor protein (APP). As Abeta 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 beta-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 Abeta reduction with the Swedish mutation (-20%) and even less for non-mutated APP (-16%). In wild-type mice, the Abeta reduction may be even further diminished. Other metabolites of the beta-secretase pathway decreased accordingly while the alternative alpha-secretase pathway increased. Complete BACE1 deletion strongly enhanced these changes. The remaining Abeta signal also described by others can be explained by assay cross-reactivity with other APP metabolites supporting BACE1 as the major beta-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 Abeta generation. |
