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The Alzheimer's disease β-secretase enzyme, BACE1

The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is ce...

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Detalles Bibliográficos
Autores principales: Cole, Sarah L, Vassar, Robert
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211305/
https://www.ncbi.nlm.nih.gov/pubmed/18005427
http://dx.doi.org/10.1186/1750-1326-2-22
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author Cole, Sarah L
Vassar, Robert
author_facet Cole, Sarah L
Vassar, Robert
author_sort Cole, Sarah L
collection PubMed
description The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of β-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing β-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences), and the pathogenic alterations in BACE1 that are observed in the diseased state.
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spelling pubmed-22113052008-01-19 The Alzheimer's disease β-secretase enzyme, BACE1 Cole, Sarah L Vassar, Robert Mol Neurodegener Review The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of β-amyloid. BACE1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of β-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing β-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences), and the pathogenic alterations in BACE1 that are observed in the diseased state. BioMed Central 2007-11-15 /pmc/articles/PMC2211305/ /pubmed/18005427 http://dx.doi.org/10.1186/1750-1326-2-22 Text en Copyright © 2007 Cole and Vassar; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review
Cole, Sarah L
Vassar, Robert
The Alzheimer's disease β-secretase enzyme, BACE1
title The Alzheimer's disease β-secretase enzyme, BACE1
title_full The Alzheimer's disease β-secretase enzyme, BACE1
title_fullStr The Alzheimer's disease β-secretase enzyme, BACE1
title_full_unstemmed The Alzheimer's disease β-secretase enzyme, BACE1
title_short The Alzheimer's disease β-secretase enzyme, BACE1
title_sort alzheimer's disease β-secretase enzyme, bace1
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211305/
https://www.ncbi.nlm.nih.gov/pubmed/18005427
http://dx.doi.org/10.1186/1750-1326-2-22
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