Abstract
γ-Secretase is a multi-protein complex that proteolyzes the transmembrane region of the amyloid β-peptide (Aβ) precursor (APP), producing the Aβ peptide implicated in the pathogenesis of Alzheimers disease (AD). This protease has been a top target for AD, and various inhibitors have been identified, including transition-state analogue inhibitors that interact with the active site, helical peptides that interact with the initial substrate docking site, and other less peptidelike, more drug-like compounds. Although one γ-secretase inhibitor has advanced into late-phase clinical trials, concerns about inhibiting this protease remain. The protease complex cleaves a number of other substrates, and in vivo toxicities observed with γ-secretase inhibitors are apparently due to blocking one particularly important substrate, the Notch receptor. Thus, the potential of γ-secretase as therapeutic target likely depends on the ability to selectively inhibit Aβ production without hindering Notch proteolysis (i.e., modulation rather than inhibition). The discovery of γ-secretase modulators has revived γ-secretase as an attractive target and has so far resulted in one compound in late-phase clinical trials. The identification of other modulators in a variety of structural classes raise the hope that more promising agents will soon be in the pipeline.
Current Alzheimer Research
Title: γ-Secretase Inhibition and Modulation for Alzheimers Disease
Volume: 5 Issue: 2
Author(s): Michael S. Wolfe
Affiliation:
Abstract: γ-Secretase is a multi-protein complex that proteolyzes the transmembrane region of the amyloid β-peptide (Aβ) precursor (APP), producing the Aβ peptide implicated in the pathogenesis of Alzheimers disease (AD). This protease has been a top target for AD, and various inhibitors have been identified, including transition-state analogue inhibitors that interact with the active site, helical peptides that interact with the initial substrate docking site, and other less peptidelike, more drug-like compounds. Although one γ-secretase inhibitor has advanced into late-phase clinical trials, concerns about inhibiting this protease remain. The protease complex cleaves a number of other substrates, and in vivo toxicities observed with γ-secretase inhibitors are apparently due to blocking one particularly important substrate, the Notch receptor. Thus, the potential of γ-secretase as therapeutic target likely depends on the ability to selectively inhibit Aβ production without hindering Notch proteolysis (i.e., modulation rather than inhibition). The discovery of γ-secretase modulators has revived γ-secretase as an attractive target and has so far resulted in one compound in late-phase clinical trials. The identification of other modulators in a variety of structural classes raise the hope that more promising agents will soon be in the pipeline.
Export Options
About this article
Cite this article as:
Wolfe S. Michael, γ-Secretase Inhibition and Modulation for Alzheimers Disease, Current Alzheimer Research 2008; 5 (2) . https://dx.doi.org/10.2174/156720508783954767
DOI https://dx.doi.org/10.2174/156720508783954767 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
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
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
Deep Learning for Advancing Alzheimer's Disease Research
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
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...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
-
Linking Alzheimer’s Disease and Type 2 Diabetes Mellitus via Aberrant Insulin Signaling and Inflammation
CNS & Neurological Disorders - Drug Targets A Pharmacological Review of Five Widely Used Traditional Medicinal Plants for Sedative-Hypnotic Effects in Bangladesh
Current Traditional Medicine Arundic Acid a Potential Neuroprotective Agent: Biological Development and Syntheses
Current Medicinal Chemistry A Theoretical Study of Substitution Effect on an Electrocyclization Reaction
Combinatorial Chemistry & High Throughput Screening Nutritional Overview on the Management of Type 2 Diabetes and the Prevention of its Complications
Current Diabetes Reviews Parvalbumin as a Pleomorphic Protein
Current Protein & Peptide Science Heparin-Binding Proteins (Chemokines and Defensins) and their Complexes with Glycosaminoglycans from the Solution NMR Perspective
Current Protein & Peptide Science The Natural History and Diagnosis of Nicotine Addiction
Current Pediatric Reviews Inhibition of Cyclin-Dependent Kinases - A Review of the Recent Patent Literature
Recent Patents on Anti-Cancer Drug Discovery Lead (Pb) in Alzheimer’s Dementia: A Systematic Review of Human Case- Control Studies
Current Alzheimer Research Perception or Reality of Body Weight: Which Matters the Most to Adolescents’ Emotional Well-being?
Current Psychiatry Reviews In vitro And In vivo Immunomodulating Properties of Mesenchymal Stem Cells
Recent Patents on Inflammation & Allergy Drug Discovery Chemistry, Biological Properties and SAR Analysis of Quinoxalinones
Mini-Reviews in Medicinal Chemistry 9.4T Magnetic Resonance Imaging of the Mouse Circle of Willis Enables Serial Characterization of Flow-Induced Vascular Remodeling by Computational Fluid Dynamics
Current Neurovascular Research Clomiphene for the Treatment of Male Infertility: A Case Report of Mood Change and a Literature Overview
Current Drug Safety The Therapeutic Role of Lamotrigine and Topiramate in A Depressive Patient with Anxiety Symptoms and Cognitive Decline: Neurometabolic Correlates
Current Clinical Pharmacology L-Type Voltage-Dependent Calcium Channels As Therapeutic Targets for Neurodegenerative Diseases
Current Medicinal Chemistry The Effects of Drugs Used in Anaesthesia on Platelet Membrane Receptors and on Platelet Function
Current Drug Targets PERK-opathies: An Endoplasmic Reticulum Stress Mechanism Underlying Neurodegeneration
Current Alzheimer Research Antimicrobial Evaluation of Erythrinan Alkaloids from Erythrina cristagalli L.
Medicinal Chemistry