Review
Function, regulation and therapeutic properties of β-secretase (BACE1)

https://doi.org/10.1016/j.semcdb.2009.01.003Get rights and content

Abstract

β-Secretase (β-site amyloid precursor protein cleaving enzyme 1; BACE1) has been identified as the rate limiting enzyme for amyloid-β-peptide (Aβ) production. Aβ is the major component of amyloid plaques and vascular deposits in Alzheimer's disease (AD) brains and believed to initiate the deadly amyloid cascade. BACE1 is the principle β-secretase, since its knock-out completely prevents Aβ generation. BACE1 is likely to process a number of different substrates and consequently several independent physiological functions may be exerted by BACE1. Currently the function of BACE1 in myelination is best understood. BACE1 cleaves and activates Neuregulin-1 and is thus directly involved in myelination of the peripheral nervous system during early postnatal development. However, additional physiological functions specifically within the central nervous system are so far less understood. BACE1 is upregulated in at least some AD brains. Multiple cellular mechanisms for BACE1 regulation are known including post-transcriptional regulation via its 5′-untranslated region, microRNA and non-coding anti-sense RNA. BACE1 is a primary target for Aβ lowering therapies, however the development of high affinity bio-available inhibitors has been a major challenge so far.

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.

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