title: BACE1 Physiological Functions May Limit Its Use as Therapeutic Target for Alzheimer's Disease.
abstract: The protease β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is required for the production of the amyloid-β (Aβ) peptide, which is central to the pathogenesis of Alzheimer's disease (AD). Chronic inhibition of this protease may temper amyloid production and cure or prevent AD. However, while BACE1 inhibitors are being pushed forward as drug candidates, a remarkable gap in knowledge on the physiological functions of BACE1 and its close homolog BACE2 becomes apparent. Here we discuss the major discoveries of the past 3 years concerning BACE1 biology and to what extent these could limit the use of BACE1 inhibitors in the clinic.
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, Universitaire Ziekenhuizen and LIND, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Soraia
authors.initials: S
authors.lastname: Barão
authors.affiliation: Neuroscience Department, Johnson & Johnson Pharmaceutical Research and Development, Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 München, Germany; Neuroproteomics, Klinikum Rechts der Isar, and Institute for Advanced Study, Technische Universität München, 81675 München, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, Universitaire Ziekenhuizen and LIND, KU Leuven, 3000 Leuven, Belgium; Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. Electronic address: Bart.DeStrooper@cme.vib-kuleuven.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse
keywords: APP; Alzheimer's disease; BACE1; C-terminal fragments; therapeutic target