Abstract
Amyloid plaques, hallmark neuropathological lesions in Alzheimers disease (AD) brain, are composed of the β-amyloid peptide (Aβ). Much evidence suggests that Aβ is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. Given the strong correlation between Aβ and AD, therapeutic strategies to lower cerebral Aβ levels should prove beneficial for AD treatment. Aβ is derived from amyloid precursor protein (APP) via cleavage by two proteases, β- and γ-secretase. The β-secretase has been identified as a novel aspartic protease named BACE1 (β-site APP Cleaving Enzyme 1) that initiates Aβ formation. Importantly, BACE1 appears to be dysregulated in AD. As the rate-limiting enzyme in Aβ generation, BACE1, in principle, is an excellent therapeutic target for strategies to reduce the production of Aβ in AD. While BACE1 knockout (BACE1-/-) mice have been instrumental in validating BACE1 as the authentic β-secretase in vivo, 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-/- mice. Here we review the basic biology of BACE1, focusing on the regulation, structure and function of this enzyme. We pay special attention to the putative function of BACE1 during normal conditions and discuss in detail the relationship that exists between key risk factors for AD and the pathogenic alterations in BACE1 that are observed in the diseased state.
Keywords: β-secretase, BACE1, Alzheimer's, β-Amyloid, APP, structure, function, risk factors
Current Alzheimer Research
Title: BACE1 Structure and Function in Health and Alzheimers Disease
Volume: 5 Issue: 2
Author(s): Sarah L. Cole and Roger Vassar
Affiliation:
Keywords: β-secretase, BACE1, Alzheimer's, β-Amyloid, APP, structure, function, risk factors
Abstract: Amyloid plaques, hallmark neuropathological lesions in Alzheimers disease (AD) brain, are composed of the β-amyloid peptide (Aβ). Much evidence suggests that Aβ is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. Given the strong correlation between Aβ and AD, therapeutic strategies to lower cerebral Aβ levels should prove beneficial for AD treatment. Aβ is derived from amyloid precursor protein (APP) via cleavage by two proteases, β- and γ-secretase. The β-secretase has been identified as a novel aspartic protease named BACE1 (β-site APP Cleaving Enzyme 1) that initiates Aβ formation. Importantly, BACE1 appears to be dysregulated in AD. As the rate-limiting enzyme in Aβ generation, BACE1, in principle, is an excellent therapeutic target for strategies to reduce the production of Aβ in AD. While BACE1 knockout (BACE1-/-) mice have been instrumental in validating BACE1 as the authentic β-secretase in vivo, 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-/- mice. Here we review the basic biology of BACE1, focusing on the regulation, structure and function of this enzyme. We pay special attention to the putative function of BACE1 during normal conditions and discuss in detail the relationship that exists between key risk factors for AD and the pathogenic alterations in BACE1 that are observed in the diseased state.
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Cite this article as:
Cole L. Sarah and Vassar Roger, BACE1 Structure and Function in Health and Alzheimers Disease, Current Alzheimer Research 2008; 5 (2) . https://dx.doi.org/10.2174/156720508783954758
DOI https://dx.doi.org/10.2174/156720508783954758 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
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Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
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Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
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