Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

Vassar, Robert; Kuhn, Peer‐Hendrik; Haass, Christian; Kennedy, Matthew E.; Rajendran, Lawrence; Wong, Philip C.; Lichtenthaler, Stefan F.

doi:10.1111/jnc.12715

Cited by 311

The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.

Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

Vassar, Robert, Kuhn, Peer‐Hendrik, Haass, Christian, Kennedy, Matthew E., Rajendran, Lawrence, Wong, Philip C., Lichtenthaler, Stefan F.·2014·Journal of Neurochemistry

DOI 10.1111/jnc.12715PMC PMC4086641

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Abstract

The β‐site APP cleaving enzymes 1 and 2 ( BACE 1 and BACE 2) were initially identified as transmembrane aspartyl proteases cleaving the amyloid precursor protein ( APP ). BACE 1 is a major drug target for Alzheimer's disease because BACE 1‐mediated cleavage of APP is the first step in the generation of the pathogenic amyloid‐β peptides. BACE 1, 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 BACE 1‐ and BACE 2‐deficient mice demonstrate a much wider range of physiological substrates and functions for both proteases within and outside of the nervous system. For BACE 1 this includes axon guidance, neurogenesis, muscle spindle formation, and neuronal network functions, whereas BACE 2 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. image 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.

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BACE1 is a major drug target in Alzheimer's disease.
“The protease BACE1 (beta-site APP cleaving enzyme) is a major drug target in Alzheimer’s disease.”
From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [1]
BACE-1 cleaves numerous substrates, conferring a wide spectrum of physiological and pathological activities.
“BACE-1 cleaves numerous substrates, which confers this enzyme a wide spectrum of physiological and pathological activities (Kuhn et al., 2012; Zhou et al., 2012; Vassar et al., 2014), but it is indisputably its ability to process APP that has attracted much attention, especially in relation to AD.”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Vassar et al., 2014
BACE1 is a major drug target in AD, but has additional substrates and thus contributes to various biological processes, which may limit its therapeutic potential.
“BACE1 is a major drug target in AD, but has additional substrates and thus contributes to various biological processes [1, 13], which may limit its therapeutic potential.”
From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [1]
A possible cause of clinical failure of β- and γ-secretase inhibitor therapies is difficulty inhibiting these proteinases without side effects from non-targeted proteolytic inhibition on their many physiological substrates.
“a possible cause of clinical failure could be the difficulty of inhibiting these proteinases without causing side effects resulting from non-targeted proteolytic inhibition on their many physiological substrates”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Vassar et al., 2014

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“However, BACE1 targeted drugdevelopment has been hindered, because the enzyme has been found to have many substrates with important physiological roles and initial nonselective inhibition of the enzyme was found to have numerous toxic consequences (76).”
Background

Authors: Vassar, R., Kuhn, P., Haass, C., Kennedy, M. E., Rajendran, L., Wong, P. C., & Lichtenthaler, S. F.
Venue: Journal of Neurochemistry
Publisher: Wiley
Published: 2014-04-19
Volume: 130
Issue: 1
Pages: 4-28
ISSN: 0022-3042
1471-4159
DOI: 10.1111/jnc.12715
PMC: PMC4086641
Cited by: 311
References: 27
Language: en
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Funders: European Research Council (FP7/2007-2013)
ERC Grant (321366)
Mrs Ammer
JPND RiMod
DAAD
NIH (R01AG022560, R01AG030142)
Cure Alzheimer's Fund
BrightFocus Foundation
Alzheimer's Association
Swiss National Science Foundation
Velux Foundation

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Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects

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