A major hallmark of @entity195 ( @entity195 ) is the deposition of @entity5357 ( @entity5357 ) peptides in amyloid plaques. @entity5357 peptides are produced by sequential cleavage of the amyloid precursor protein (APP) by the @entity19027 ( @entity19027 ) and the gamma-secretase (y-sec) complex. Pharmacological treatments that decrease brain levels of in particular the toxic Ab42 peptide are thought to be promising approaches for @entity195 modification. Potent and selective @entity19027 inhibitors as well as y-sec modulators (GSMs) have been designed. Pharmacological intervention of secretase function is not without risks of either on- or off-target adverse effects. One way of improving the therapeutic window could be to combine treatment on multiple targets, using smaller individual doses and thereby minimizing adverse effect liability. We show that combined treatment of primary cortical neurons with a @entity19027 -inhibitor and a GSM gives an additive effect on Ab42 level change compared to the individual treatments. We extend this finding to C57BL/6 @entity19 , where the combined treatment results in reduction of brain Ab42 levels reflecting the sum of the individual treatment efficacies. These results show that pharmacological targeting of two APP processing steps is feasible without negatively interfering with the mechanism of action on individual targets. We conclude that targeting @entity5357 production by combining a @entity19027 -inhibitor and a GSM could be a viable approach for therapeutical intervention in @entity195 modification. This article is protected by copyright. All rights reserved.

Combining an XXXX ( @entity5357 ) cleaving enzyme inhibitor with a y-secretase modulator results in an additive reduction of @entity5357 production.

@entity19 :: ('10090', 'Species') :: ['mice'] @entity5357 :: ('MESH:D012497', 'Disease') :: ['amyloid-beta', 'Ab'] @entity19027 :: ('23821(Tax:10090)', 'Gene') :: ['beta amyloid cleaving enzyme', 'BACE1', 'BACE'] @entity195 :: ('MESH:D000544', 'Disease') :: ['AD', "Alzheimer's disease", 'AD disease']
@entity5357 :: (MESH:D012497,Disease) :: ['amyloid-beta']
