Abstract
An effective, disease-modifying treatment of Alzheimers disease (AD) remains one of the most significant unmet needs in modern medicine. As a result of the extensive research in the area, the mechanisms underlying the disease are now much better understood than at any time before. A significant amount of evidence points to the central role of β-amyloid (Aβ) peptide-mediated toxicity in the disease etiology and strategies to remove this species from the central nervous system (CNS) have been actively pursued. The enzyme responsible for the final step in Aβ synthesis, γ-secretase, has emerged as an attractive drug target and intensive research has transformed this enzyme from shadowy beginnings into a well characterised member of a new family of intramembrane-cleaving aspartyl proteases. Many inhibitors across diverse structural classes have been discovered and have demonstrated a lowering of central Aβ levels in preclinical models of AD. It has also become increasingly evident more recently that γ-secretase also mediates a range of cleavages of alternative transmembrane peptides most notably the Notch receptor and the functional consequences of this activity have attracted much attention. The ultimate therapeutic benefit of γ-secretase inhibitors and the effect of alternative, mechanism-based activities can only be judged when clinical data is forthcoming. In this review we describe the literature regarding the discovery of the nature of γ-secretase, the development of small molecule inhibitors and their in vivo profiles.
Keywords: central nervous system, aspartyl-type protease, cyclooxygenase, elisa
Current Pharmaceutical Design
Title: γ-Secretase as a Therapeutic Target for the Treatment of Alzheimers Disease
Volume: 11 Issue: 26
Author(s): I. Churcher and D. Beher
Affiliation:
Keywords: central nervous system, aspartyl-type protease, cyclooxygenase, elisa
Abstract: An effective, disease-modifying treatment of Alzheimers disease (AD) remains one of the most significant unmet needs in modern medicine. As a result of the extensive research in the area, the mechanisms underlying the disease are now much better understood than at any time before. A significant amount of evidence points to the central role of β-amyloid (Aβ) peptide-mediated toxicity in the disease etiology and strategies to remove this species from the central nervous system (CNS) have been actively pursued. The enzyme responsible for the final step in Aβ synthesis, γ-secretase, has emerged as an attractive drug target and intensive research has transformed this enzyme from shadowy beginnings into a well characterised member of a new family of intramembrane-cleaving aspartyl proteases. Many inhibitors across diverse structural classes have been discovered and have demonstrated a lowering of central Aβ levels in preclinical models of AD. It has also become increasingly evident more recently that γ-secretase also mediates a range of cleavages of alternative transmembrane peptides most notably the Notch receptor and the functional consequences of this activity have attracted much attention. The ultimate therapeutic benefit of γ-secretase inhibitors and the effect of alternative, mechanism-based activities can only be judged when clinical data is forthcoming. In this review we describe the literature regarding the discovery of the nature of γ-secretase, the development of small molecule inhibitors and their in vivo profiles.
Export Options
About this article
Cite this article as:
Churcher I. and Beher D., γ-Secretase as a Therapeutic Target for the Treatment of Alzheimers Disease, Current Pharmaceutical Design 2005; 11 (26) . https://dx.doi.org/10.2174/138161205774370771
DOI https://dx.doi.org/10.2174/138161205774370771 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Brain Oxidative Stress - Analytical Chemistry and Thermodynamics of Glutathione and NADPH
Current Topics in Medicinal Chemistry Influence of Essential Trace Minerals and Micronutrient Insufficiencies on Harmful Metal Overload in a Mongolian Patient with Multiple Sclerosis
Current Aging Science Minocycline: Neuroprotective Mechanisms in Parkinsons Disease
Current Pharmaceutical Design Prospective Function of Different Antioxidant Containing Natural Products in the Treatment of Neurodegenerative Diseases
CNS & Neurological Disorders - Drug Targets Pharmacodynamics of Memantine: An Update
Current Neuropharmacology Chondroitin Sulfate, a Major Niche Substance of Neural Stem Cells, and Cell Transplantation Therapy of Neurodegeneration Combined with Niche Modification
Current Stem Cell Research & Therapy Recent Advances in the Development of Selective CB2 Agonists as Promising Anti-Inflammatory Agents
Current Medicinal Chemistry Lactoferrin as a Natural Immune Modulator
Current Pharmaceutical Design YKL-40 as a Potential Biomarker and a Possible Target in Therapeutic Strategies of Alzheimer’s Disease
Current Neuropharmacology Importance of Zebrafish as an Efficient Research Model for the Screening of Novel Therapeutics in Neurological Disorders
CNS & Neurological Disorders - Drug Targets On the Design of Broad Based Screening Assays to Identify Potential Pharmacological Chaperones of Protein Misfolding Diseases
Current Topics in Medicinal Chemistry Progress in Multiple Sclerosis Genetics
Current Genomics The Endocannabinoid System and Multiple Sclerosis
Current Pharmaceutical Design Cytokine-Induced Depression: Current Status and Novel Targets for Depression Therapy
CNS & Neurological Disorders - Drug Targets Agonism of Peroxisome Proliferator Receptor-Gamma may have Therapeutic Potential for Neuroinflammation and Parkinsons Disease
Current Neuropharmacology Interactions of VDAC with Proteins Involved in Neurodegenerative Aggregation: An Opportunity for Advancement on Therapeutic Molecules
Current Medicinal Chemistry TNF α Signaling Beholds Thalidomide Saga: A Review of Mechanistic Role of TNF-α Signaling Under Thalidomide
Current Topics in Medicinal Chemistry Extracellular Vesicles, Stem Cells and the Role of miRNAs in Neurodegeneration
Current Neuropharmacology Molecular Basis of Human Diseases and Targeted Therapy Based on Small-Molecule Inhibitors of ER Stress-Induced Signaling Pathways
Current Molecular Medicine Targeting Mitochondria in Fighting Cancer
Current Pharmaceutical Design