title: Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and presenilin.
abstract: Alzheimer's disease causing mutations in the amyloid precursor protein (APP) or in the Presenilin 1 (PS1) or Presenilin 2 (PS2) genes increase the production of amyloid peptides (Aβ) that precipitate in amyloid plaques. Since amyloid plaques are also a prominent feature of sporadic Alzheimer's disease (AD), abnormal proteolysis of APP and the generation of amyloid beta (Aβ) are key events in the pathogenesis of AD. The proteases (secretases) that cleave APP are therefore important therapeutic targets, both for the rare familial forms but likely also for the sporadic forms of AD. The identification and understanding of the (neuro)biological functions of the α-, β-, and presenilin/γ-secretase (complexes) is important for the development of drugs and the delineation of their associated side effects. The potential impact of this type of research exceeds the AD field since the function of these secretases are also linked to cellular pathways like ectodomain shedding of growth factors and regulated intramembrane proteolysis of receptors in developmental biology, tissue homeostasis, and tumorigenesis. The generation of mice deficient in presenilin 1, presenilin 2, the α-secretase ADAM10, and the β-secretases BACE1 and BACE2 were instrumental for the elucidation of the physiological functions of these proteases. Using these mouse models understanding how these secretases regulate amyloid peptide formation and how they exert their diverse biological functions could be significantly increased. This review attempts to summarize selected aspects of the current view of the multiple roles such proteases play in health and disease.
authors: Biochemical Institute, Christian-Albrechts-University Kiel, Olshausenstr. 40, 24098 Kiel, Germany.
authors: Johannes
authors: J
authors: Prox
authors: Andrea
authors: A
authors: Rittger
authors: Paul
authors: P
authors: Saftig
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008959:Models, Neurological; D009434:Neural Pathways / Q000502:physiology; D053764:Presenilin-1 / Q000502:physiology; D053766:Presenilin-2 / Q000502:physiology
chemical_list: C509285:Bace2 protein, mouse; D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse