Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects
| Autor: | Matthew E. Kennedy, Peer-Hendrik Kuhn, Stefan F. Lichtenthaler, Philip C. Wong, Robert Vassar, Lawrence Rajendran, Christian Haass |
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| Přispěvatelé: | University of Zurich, Lichtenthaler, Stefan F |
| Rok vydání: | 2014 |
| Předmět: |
Intracellular Fluid
1303 Biochemistry medicine.medical_treatment 2804 Cellular and Molecular Neuroscience antagonists & inhibitors [Amyloid Precursor Protein Secretases] Biochemistry APP protein human Amyloid beta-Protein Precursor 0302 clinical medicine Amyloid precursor protein drug therapy [Alzheimer Disease] Aspartic Acid Endopeptidases 0303 health sciences biology 11359 Institute for Regenerative Medicine (IREM) antagonists & inhibitors [Aspartic Acid Endopeptidases] Cell biology Protein Transport Alzheimer's disease Proteases physiology [Amyloid beta-Protein Precursor] 610 Medicine & health Article drug effects [Intracellular Fluid] 03 medical and health sciences Cellular and Molecular Neuroscience Alzheimer Disease BACE1 protein human mental disorders medicine Animals Humans physiology [Amyloid Precursor Protein Secretases] ddc:610 Neuregulin 1 030304 developmental biology Protease enzymology [Alzheimer Disease] medicine.disease physiology [Aspartic Acid Endopeptidases] biology.protein Verubecestat physiology [Protein Transport] Axon guidance Amyloid Precursor Protein Secretases enzymology [Intracellular Fluid] Neuroscience Amyloid precursor protein secretase 030217 neurology & neurosurgery Forecasting |
| Zdroj: | Journal of neurochemistry 130(1), 4-28 (2014). doi:10.1111/jnc.12715 Journal of Neurochemistry |
| ISSN: | 0022-3042 |
| DOI: | 10.1111/jnc.12715 |
| Popis: | The β-site APP cleaving enzymes 1 and 2 (BACE1 and BACE2) were initially identified as transmembrane aspartyl proteases cleaving the amyloid precursor protein (APP). BACE1 is a major drug target for Alzheimer's disease because BACE1-mediated cleavage of APP is the first step in the generation of the pathogenic amyloid-β peptides. BACE1, which is highly expressed in the nervous system, is also required for myelination by cleaving neuregulin 1. Several recent proteomic and in vivo studies using BACE1- and BACE2-deficient mice demonstrate a much wider range of physiological substrates and functions for both proteases within and outside of the nervous system. For BACE1 this includes axon guidance, neurogenesis, muscle spindle formation, and neuronal network functions, whereas BACE2 was shown to be involved in pigmentation and pancreatic β-cell function. This review highlights the recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE inhibitors in Alzheimer's disease. The protease BACE1 is a major drug target in Alzheimer disease. Together with its homolog BACE2, both proteases have an increasing number of functions within and outside of the nervous system. This review highlights recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE inhibitors in Alzheimer disease. |
| Databáze: | OpenAIRE |
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