Abstract
Accumulation and deposition of beta amyloid (Aβ) play a critical role in the pathogenesis of Alzheimers Disease (AD), and numerous approaches to control Aβ aggregation are being actively pursued. Brain Aβ levels are controlled by the action of several proteolytic enzymes such as neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin. While up-regulation of these enzymes increased clearance of Aβ in transgenic mouse models of AD, these enzymes have other natural substrates and multiple cleavage sites in Aβ complicating their use for treating AD. Alternatively, immunotherapeutic approaches to clear Aβ are gaining interest. Active and passive immunization studies with Aβ can reduce plaque burden and memory loss, but clinical trials were stopped due to meningioencephalitis in some patients. Naturally occurring proteolytic antibodies have been shown to cleave Aβ, and their serum titers are increased in patients with AD reflecting a protective autoimmune response. These antibodies however cannot cross the blood brain barrier and depend entirely on peripheral clearance to clear Aβ. A potentially non-inflammatory approach to facilitate Aβ clearance and reduce toxicity is to promote hydrolysis of Aβ at its α-secretase site using affinity matured single chain antibody fragments (scFvs). Bispecific antibodies consisting of a proteolytic scFv and a targeting scFv can be engineered to selectively supplement and target extracellular α-secretase activity and to target toxic Aβ forms facilitating their degradation and clearance without generating an immune response. This strategy represents a suitable paradigm for treating other neurological diseases such as Parkinsons Disease, Lou Gehrigs Disease, and spongiform encephalopathies.
Keywords: Beta amyloid cleavage, α-secretase, proteolytic scFv, serine protease, bispecific scFv
Current Alzheimer Research
Title: Targeted Hydrolysis of Beta-Amyloid with Engineered Antibody Fragments
Volume: 7 Issue: 3
Author(s): S. Kasturirangan and M. Sierks
Affiliation:
Keywords: Beta amyloid cleavage, α-secretase, proteolytic scFv, serine protease, bispecific scFv
Abstract: Accumulation and deposition of beta amyloid (Aβ) play a critical role in the pathogenesis of Alzheimers Disease (AD), and numerous approaches to control Aβ aggregation are being actively pursued. Brain Aβ levels are controlled by the action of several proteolytic enzymes such as neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin. While up-regulation of these enzymes increased clearance of Aβ in transgenic mouse models of AD, these enzymes have other natural substrates and multiple cleavage sites in Aβ complicating their use for treating AD. Alternatively, immunotherapeutic approaches to clear Aβ are gaining interest. Active and passive immunization studies with Aβ can reduce plaque burden and memory loss, but clinical trials were stopped due to meningioencephalitis in some patients. Naturally occurring proteolytic antibodies have been shown to cleave Aβ, and their serum titers are increased in patients with AD reflecting a protective autoimmune response. These antibodies however cannot cross the blood brain barrier and depend entirely on peripheral clearance to clear Aβ. A potentially non-inflammatory approach to facilitate Aβ clearance and reduce toxicity is to promote hydrolysis of Aβ at its α-secretase site using affinity matured single chain antibody fragments (scFvs). Bispecific antibodies consisting of a proteolytic scFv and a targeting scFv can be engineered to selectively supplement and target extracellular α-secretase activity and to target toxic Aβ forms facilitating their degradation and clearance without generating an immune response. This strategy represents a suitable paradigm for treating other neurological diseases such as Parkinsons Disease, Lou Gehrigs Disease, and spongiform encephalopathies.
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Cite this article as:
Kasturirangan S. and Sierks M., Targeted Hydrolysis of Beta-Amyloid with Engineered Antibody Fragments, Current Alzheimer Research 2010; 7 (3) . https://dx.doi.org/10.2174/156720510791050876
DOI https://dx.doi.org/10.2174/156720510791050876 |
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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