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Handbook of Neurochemistry and Molecular Neurobiology pp 261–284Cite as

Alzheimer's Disease BACE Proteases

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Abstract:

The aberrant proteolytical processing of the amyloid precursor protein (APP) gives rise to β-amyloid peptides, which accumulate as perivascular or parenchymal deposits in brains of Alzheimer's disease (AD) patients. The generation of β-amyloid peptides is initiated by APP cleavage by an aspartyl protease named beta-site APP-cleaving enzyme 1 (BACE1), followed by γ-secretase cleavage. The discovery of BACE1 some years ago and subsequent studies on the regulation of its expression and enzymatic activity allowed for a better understanding of APP processing, β-amyloid generation and the pathogenesis of AD in general. Some of the unique features of BACE1, such as regulatory elements in the 5′ region of BACE1 mRNA and factors that contribute to its cell type-specific activation helped to explain epidemiological observations and opened new rational therapeutic opportunities. However, although BACE1 has been shown to be the only protease in brain with significant β-secretase activity, there are a number of alternative substrates in addition to APP, indicating that a careful estimation of possible side effects of BACE1 inhibitors is required. Nevertheless, experimental data from transgenic mouse models of AD, BACE1 knockout mice and pharmacological studies corroborate the potential usefulness of drugs that interfere with BACE1 expression and/or enzymatic activity for the treatment of AD.

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Abbreviations

Aβ:

β-amyloid peptide

AD:

Alzheimer's disease

ADAM:

a disintegrin and metalloprotease

APLP:

amyloid precursor-like protein

APP:

amyloid precursor protein

BACE:

beta-site APP-cleaving enzyme

CCS:

copper chaperone for superoxide dismutase-1

ChAT:

choline acetyltransferase

DS:

Down's syndrome

ER:

endoplasmatic reticulum

FAD:

familial forms of Alzheimer's disease

GFAP:

glial fibrillary acidic protein

GGA:

Golgi-localized γ-ear-containing ARF binding

HEK:

human embryonic kidney

MDCK:

Madin-Darby canine kidney

NSAIDs:

nonsteroidal anti-inflammatory drugs

PLSCR 1:

phospholipid scramblase 1

PPARγ:

peroxisome proliferator-activated receptor-γ

PPRE:

PPARγ responsive element

pro:

prodomain

RTN3:

reticulon 3

RTN4b:

reticulon 4b

TGN:

trans-Golgi network

SP:

signal peptide

TACE:

tumor necrosis factor α-converting enzyme

TMD:

transmembrane domain

5′UTR:

5′ untranslated region

uORF:

upstream open reading frame

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Authors
  1. S. Roßner
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  2. S. F. Lichtenthaler
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Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 10962, 140 Old Orangeburg Road, Orangeburg, New York, USA

    Abel Lajtha (Director) (Director)

  2. Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, 301 University Blvd., TX, 77555, Galveston, USA

    J. Regino Perez-Polo (I. H. Kempner Professor and Chair Dept. Biochemistry & Molecular Biology Senior Scientist Sealy Center for Molecular Medicine Staff Scientist Shriner's Hospital for Children) (I. H. Kempner Professor and Chair Dept. Biochemistry & Molecular Biology Senior Scientist Sealy Center for Molecular Medicine Staff Scientist Shriner's Hospital for Children)

  3. Universität Leipzig Medizinische Fakultät, Paul-Flechsig-Institut für Hirnforschung, Jahnallee 59, 04109, Leipzig, Germany

    Steffen Rossner

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Roßner, S., Lichtenthaler, S.F. (2008). Alzheimer's Disease BACE Proteases. In: Lajtha, A., Perez-Polo, J.R., Rossner, S. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-32671-9_11

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