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Combining an amyloid‐beta (Aβ) cleaving enzyme inhibitor with a γ‐secretase modulator results in an additive reduction of Aβ production
Author(s) -
Strömberg Kia,
Eketjäll Susanna,
Georgievska Biljana,
Tunblad Karin,
Eliason Kristina,
Olsson Fredrik,
Radesäter AnnCathrin,
Klintenberg Rebecka,
Arvidsson Per I.,
Berg Stefan,
Fälting Johanna,
Cowburn Richard F.,
Dabrowski Michael
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13103
Subject(s) - amyloid precursor protein secretase , gamma secretase , amyloid (mycology) , amyloid precursor protein , chemistry , pharmacology , amyloid beta , enzyme , p3 peptide , peptide , biochemistry , alzheimer's disease , medicine , disease , inorganic chemistry
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 BACE 1 inhibitors as well as γ‐sec modulators ( GSM s) 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 BACE 1 inhibitor and a GSM gives an additive effect on Aβ42 level change compared with the individual treatments. We extend this finding to C57 BL /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.