title: The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain.
abstract: Proteins belonging to the 'A Disintegrin And Metalloproteinase' (ADAM) family are membrane-anchored proteases that are able to cleave the extracellular domains of several membrane-bound proteins in a process known as 'ectodomain shedding'. In the central nervous system, ADAM10 has attracted the most attention, since it was described as the amyloid precursor protein α-secretase over ten years ago. Despite the excitement over the potential of ADAM10 as a novel drug target in Alzheimer disease, the physiological functions of ADAM10 in the brain are not yet well understood. This is largely because of the embryonic lethality of ADAM10-deficient mice, which results from the loss of cleavage and signaling of the Notch receptor, another ADAM10 substrate. However, the recent generation of conditional ADAM10-deficient mice and the identification of further ADAM10 substrates in the brain has revealed surprisingly numerous and fundamental functions of ADAM10 in the development of the embryonic brain and also in the homeostasis of adult neuronal networks. Mechanistically, ADAM10 controls these functions by utilizing unique postsynaptic substrates in the central nervous system, in particular synaptic cell adhesion molecules, such as neuroligin-1, N-cadherin, NCAM, Ephrin A2 and A5. Consequently, a dysregulation of ADAM10 activity is linked to psychiatric and neurological diseases, such as epilepsy, fragile X syndrome and Huntington disease. This review highlights the recent progress in understanding the substrates and function as well as the regulation and cell biology of ADAM10 in the central nervous system and discusses the value of ADAM10 as a drug target in brain diseases.
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany. Electronic address: psaftig@biochem.uni-kiel.de.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), and Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Strasse 17, D-81377 München, Germany; Neuroproteomics, Klinikum rechts der Isar, and Institute for Advanced Study, Technische Universität München, 81675 Munich, Germany. Electronic address: stefan.lichtenthaler@dzne.de.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D006801:Humans
chemical_list: D053829:Amyloid Precursor Protein Secretases
keywords: ADAM; APP; Alzheimer disease; Axon; Cell adhesion; Ectodomain shedding; Neurite outgrowth; Neuronal differentiation; Notch-1; Post synapse; Prion; Protease; Signaling; Synaptogenesis; Therapy