title: Combining an amyloid-beta (Aβ) cleaving enzyme inhibitor with a γ-secretase modulator results in an additive reduction of Aβ production.
abstract: A major hallmark of Alzheimer's disease (AD) is the deposition of amyloid-β (Aβ) peptides in amyloid plaques. Aβ peptides are produced by sequential cleavage of the amyloid precursor protein by the β amyloid cleaving enzyme (BACE) and the γ-secretase (γ-sec) complex. Pharmacological treatments that decrease brain levels of in particular the toxic Aβ42 peptide are thought to be promising approaches for AD disease modification. Potent and selective BACE1 inhibitors as well as γ-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 BACE1 inhibitor and a GSM gives an additive effect on Aβ42 level change compared with the individual treatments. We extend this finding to C57BL/6 mice, where the combined treatment results in reduction of brain Aβ42 levels reflecting the sum of the individual treatment efficacies. These results show that pharmacological targeting of two amyloid precursor protein processing steps is feasible without negatively interfering with the mechanism of action on individual targets. We conclude that targeting Aβ production by combining a BACE inhibitor and a GSM could be a viable approach for therapeutic intervention in AD modification.
authors.affiliation: Department of Neuroscience, AstraZeneca R&D, CNS/Pain iMED, Södertälje, Sweden.
authors.forename: Kia
authors.initials: K
authors.lastname: Strömberg
authors.forename: Susanna
authors.initials: S
authors.lastname: Eketjäll
authors.forename: Biljana
authors.initials: B
authors.lastname: Georgievska
authors.forename: Karin
authors.initials: K
authors.lastname: Tunblad
authors.forename: Kristina
authors.initials: K
authors.lastname: Eliason
authors.forename: Fredrik
authors.initials: F
authors.lastname: Olsson
authors.forename: Ann-Cathrin
authors.initials: AC
authors.lastname: Radesäter
authors.forename: Rebecka
authors.initials: R
authors.lastname: Klintenberg
authors.forename: Per I
authors.initials: PI
authors.lastname: Arvidsson
authors.forename: Stefan
authors.initials: S
authors.lastname: von Berg
authors.forename: Johanna
authors.initials: J
authors.lastname: Fälting
authors.forename: Richard F
authors.initials: RF
authors.lastname: Cowburn
authors.forename: Michael
authors.initials: M
authors.lastname: Dabrowski
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011714:Pyrans / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C572499:AZ4800; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011714:Pyrans; D011743:Pyrimidines; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer's disease; amyloid beta peptides; beta amyloid cleaving enzyme; gamma-secretase complex