ReviewFunction, regulation and therapeutic properties of β-secretase (BACE1)
Section snippets
Maturation and cellular localization of BACE1
The identification of the aspartyl protease BACE1 as β-secretase allowed the rapid characterization of this enzyme. Purified BACE1 has an optimal enzymatic activity at an acidic pH of approximately 4.5, which reflects its primary site of action inside the cell, i.e. in acidified endosomes [6], [14], [33]. However, APP containing the Swedish mutation is, due to the better cleavage site, already cleaved within the Golgi apparatus, thus allowing BACE1 to outcompete anti-amyloidogenic processing by
BACE1 substrates
BACE1 knock-out mice fail to produce any Aβ, thus BACE1 is the sole enzyme with a bonafide β-secretase activity. These mice develop normally, are healthy, fertile and appear to have no obvious morphological phenotype [62], [63], [64], [65], [66]. This finding suggests that inhibition of BACE1 could be a useful therapeutic approach for the treatment of AD, since a blockade of BACE1 activity should not interfere too much with physiological mechanisms exerted by BACE1 cleavage products. However,
Regulation of BACE1 expression
The regulation of BACE1 at the transcriptional level was studied mainly in vitro so far [92], [93], [94], [95], [96], [97]. Several promoter elements important for the transcriptional regulation of BACE1, e.g. transcription factor binding sites for signal transducer and activator of transcription (STAT1/3 and STAT6) have been identified in the BACE1 promoter [94], [98]. Recently it was found that overexpression of p25, the activator of cyclin dependent kinase 5 (CDK5), results in a 2-fold
BACE1 directed therapy
Both amyloidogenic secretases, BACE1 and γ-secretase, are attractive and obvious targets for the therapeutic treatment of AD. It was shown that BACE1 seems to prefer more bulky residues at P1, like in APPswe [125], therefore wild type APP is rather inefficiently cleaved by BACE1 [126], [127]. While the KM to NL exchange at the β-secretase cleavage site in APPswe results in an increased affinity for BACE1, a M to V substitution at the position P1 reduced the affinity significantly [125]. From
Acknowledgements
The authors thank Dr. Richard Page for comments on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (DFG), the Leibniz Award (to C.H.), the SFB596 (Project A9; to C.H., S. L. and M.W.), the National Genome Research Network (NGFNplus; to C.H.), the Helmholtz Alliance for Mental Health and Ageing (HELMA; to C.H. and M.W.) and the Virtual Institute Neurodegeneration & Ageing (to C.H.). C.H. is supported by a Forschungsprofessur of the Ludwig-Maximilians-University.
References (136)
- et al.
Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein
Biochem Biophys Res Commun
(1984) - et al.
Identification of a novel aspartic protease (Asp 2) as beta-secretase
Mol Cell Neurosci
(1999) - et al.
A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta-secretase
J Biol Chem
(2000) - et al.
Promotion of BACE1 mRNA alternative splicing reduces amyloid beta-peptide production
J Biol Chem
(2008) - et al.
Intramembrane proteolysis by gamma-secretase
J Biol Chem
(2008) - et al.
Dissection of amyloid-beta precursor protein-dependent transcriptional transactivation
J Biol Chem
(2004) - et al.
Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP
Neuron
(2005) The blood–brain barrier in health and chronic neurodegenerative disorders
Neuron
(2008)- et al.
Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor
J Biol Chem
(1998) - et al.
Expression analysis of BACE2 in brain and peripheral tissues
J Biol Chem
(2000)
ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site
Mol Cell Neurosci
BACE2 functions as an alternative alpha-secretase in cells
J Biol Chem
Evidence that production and release of amyloid beta-protein involves the endocytic pathway
J Biol Chem
Metabolism of the “Swedish” amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the “beta-secretase” site occurs in the golgi apparatus
J Biol Chem
Dimerization of beta-site beta-amyloid precursor protein-cleaving enzyme
J Biol Chem
Human BACE forms dimers and colocalizes with APP
J Biol Chem
Characterization of Alzheimer's beta-secretase protein BACE. A pepsin family member with unusual properties
J Biol Chem
Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase
J Biol Chem
Maturation and pro-peptide cleavage of beta-secretase
J Biol Chem
Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production
J Biol Chem
A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta-secretase
J Biol Chem
Processing of beta-secretase by furin and other members of the proprotein convertase family
J Biol Chem
Characterization of the glycosylation profiles of Alzheimer's beta-secretase protein Asp-2 expressed in a variety of cell lines
J Biol Chem
The metabolism of beta-amyloid converting enzyme and beta-amyloid precursor protein processing
Biochem Biophys Res Commun
Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts
Curr Biol
The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total A(beta)
Mol Cell Neurosci
Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2
J Biol Chem
GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network
Mol Cell Neurosci
GGA proteins mediate the recycling pathway of memapsin 2 (BACE)
J Biol Chem
BACE is degraded via the lysosomal pathway
J Biol Chem
Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity
Neuron
The beta-amyloid-related proteins presenilin 1 and BACE1 are axonally transported to nerve terminals in the brain
Exp Neurol
APP processing and synaptic function
Neuron
BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time
Neurobiol Dis
BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes
Mol Cell Neurosci
Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice
J Biol Chem
BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease
Neuron
Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system
Neuron
Stimulated ErbB4 internalization is necessary for neuregulin signaling in neurons
Biochem Biophys Res Commun
Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme
Mol Cell Neurosci
NRG1 and synaptic function in the CNS
Neuron
Neuregulin-1 enhances depolarization-induced GABA release
Neuron
The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity
Neuron
beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase
J Biol Chem
In vivo cleavage of alpha2,6-sialyltransferase by Alzheimer beta-secretase
J Biol Chem
The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1
J Biol Chem
Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase
J Biol Chem
Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing
Neuron
Oxidative stress increases expression and activity of BACE in NT(2) neurons
Neurobiol Dis
The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
Science
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