The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer’s Disease and Beyond

German Center for Neurodegenerative Diseases (DZNE) Munich, Germany.
Frontiers in Physiology (Impact Factor: 3.53). 02/2012; 3:8. DOI: 10.3389/fphys.2012.00008
Source: PubMed


The β-site APP cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis and in myelination. BACE1 initiates the generation of the pathogenic amyloid β-peptide, which makes BACE1 a major drug target for AD. BACE1 also cleaves and activates neuregulin 1, thereby contributing to postnatal myelination, in particular in the peripheral nervous system. Additional proteins are also cleaved by BACE1, but less is known about the physiological consequences of their cleavage. Recently, new phenotypes were described in BACE1-deficient mice. Although it remains unclear through which BACE1 substrates they are mediated, the phenotypes suggest a versatile role of this protease for diverse physiological processes. This review summarizes the enzymatic and cellular properties of BACE1 as well as its regulation by lipids, by transcriptional, and by translational mechanisms. The main focus will be on the recent progress in understanding BACE1 function and its implication for potential mechanism-based side effects upon therapeutic inhibition.

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    • "e l s e v i e r . c o m / l o ca t e / n e u a g i n g 2006; Dislich and Lichtenthaler, 2012; Hicks et al., 2012; Vetrivel and Thinakaran, 2010). Systematic anatomic study of cases with AD-related pathology has prompted a staging classification of sporadic AD. "
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    • "Finally, we discuss the therapeutic potential of both proteases , highlight the current therapeutic development for BACE1 in Alzheimer's disease (AD) and give an outlook on future BACE protease research. Regulation of BACE protease expression and activity has been partly reviewed elsewhere (Dislich and Lichtenthaler 2012; Rossner et al. 2006) and is not the topic of this review article. b-amyloid and Alzheimer's disease AD is a devastating neurodegenerative disease characterized by the cerebral accumulation of two hallmark brain lesions: amyloid plaques and neurofibrillary tangles. "
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    ABSTRACT: 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 (AD) 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 AD.This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 03/2014; 130(1). DOI:10.1111/jnc.12715 · 4.28 Impact Factor
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    • "KO-mice showed subtle neurochemical deficits and behavioral changes Dominguez et al., 2005 Cleaved APP ectodomain involvement in normal nerve cells and Aβ peptides dampening neuronal hyperactivity Ma et al., 2007 Sixty-eight epithelial cell line substrates detected, many membrane-anchored and involved in contact-dependent intercellular communication Hemming et al., 2009 Voltage-gated sodium channel subunits (SCN4B, O60939 and related subunits) substrates for regulation of Nav1 channel metabolism Kovacs et al., 2010 Neuregulin, NRG1, Q022979, substrate for control of nerve cell myelination Fleck et al., 2012 Amyloid-like protein 2 (APP2, Q06481) substrate for ectodomain fragments Hogl et al., 2011 Brain substrates in inhibitor-treated and KO mice involved in neurites and synapses Kuhn et al., 2012 Thirteen non-amyloidogenic substrates reviewed Dislich and Lichtenthaler, 2012 Pancreatic ectodomain shedding regulates broad set of β-cell-enriched substrates Stützer et al., 2013 Zebrafish KO indicates substrates related to neurite outgrowth and axon guidance, including plexin A3, B0S5N4, and glypican-1 (F1QCC6) Hogl et al., 2013 Zebrafish KO shows peripheral hypomyelination Van Bebber et al., 2013 BACE2 Processes APP at the beta-secretase site Hussain et al., 2000 Tissue distribution implies functions distinct from neuronal BACE1 Sun et al., 2005 KO mice normal but neonatal mortality increase in BACE1/2 double-KO Dominguez et al., 2005 Processes APP but reduces Aβ production Sun et al., 2006 Secretase of the plasma membrane protein TMM27 (Q9HBJ8) in mice and in human β cells Esterhazy et al., 2011 Pancreatic ectodomain shedding regulates narrow set of β-cell-enriched substrates, including SEZ6L (Q9BYH1) and SEZ6L2 (Q6UXD5) Stützer et al., 2013 Role in processing mouse pigment cell-specific Melanocyte Protein, PMEL, Q60696 Rochin et al., 2013 Zebrafish KO melanocyte migration phenotype. Double KO (Bace1 −/− ; Bace2 −/− ) viable and does not enhance the single mutant phenotypes, indicating non-redundant functions in fish "
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    ABSTRACT: The beta amyloid (APP) cleaving enzyme (BACE1) has been a drug target for Alzheimer's Disease (AD) since 1999 with lead inhibitors now entering clinical trials. In 2011, the paralog, BACE2, became a new target for type II diabetes (T2DM) having been identified as a TMEM27 secretase regulating pancreatic β cell function. However, the normal roles of both enzymes are unclear. This study outlines their evolutionary history and new opportunities for functional genomics. We identified 30 homologs (UrBACEs) in basal phyla including Placozoans, Cnidarians, Choanoflagellates, Porifera, Echinoderms, Annelids, Mollusks and Ascidians (but not Ecdysozoans). UrBACEs are predominantly single copy, show 35-45% protein sequence identity with mammalian BACE1, are ~100 residues longer than cathepsin paralogs with an aspartyl protease domain flanked by a signal peptide and a C-terminal transmembrane domain. While multiple paralogs in Trichoplax and Monosiga pre-date the nervous system, duplication of the UrBACE in fish gave rise to BACE1 and BACE2 in the vertebrate lineage. The latter evolved more rapidly as the former maintained the emergent neuronal role. In mammals, Ka/Ks for BACE2 is higher than BACE1 but low ratios for both suggest purifying selection. The 5' exons show higher Ka/Ks than the catalytic section. Model organism genomes show the absence of certain BACE human substrates when the UrBACE is present. Experiments could thus reveal undiscovered substrates and roles. The human protease double-target status means that evolutionary trajectories and functional shifts associated with different substrates will have implications for the development of clinical candidates for both AD and T2DM. A rational basis for inhibition specificity ratios and assessing target-related side effects will be facilitated by a more complete picture of BACE1 and BACE2 functions informed by their evolutionary context.
    Frontiers in Genetics 12/2013; 4:293. DOI:10.3389/fgene.2013.00293
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