Abstract
Accumulation of the amyloid β-peptide (Aβ) in the brain is believed to initiate a series of neurotoxic events that causes neurodegeneration in Alzheimer´s disease (AD). Aβ is generated by processing of the β-amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, β-secretase and γ-secretase. While β-secretase has been identified as the membrane-bound aspartyl protease BACE, the identity of γ-secretase, which catalyzes the final, intramembrane cleavage of APP as well as of several other type I transmembrane proteins, has been enigmatic for a long time. Exciting progress has been made in the past year towards its uncovering. Genetics paved the way for subsequent biochemical reconstitution studies that demonstrated that γ-secretase is a protein complex composed of presenilin (PS), nicastrin (NCT), APH-1 and PEN-2. Thus, the complete set of genes that is required to generate Aβ from its precursor has now ultimately been identified. PS carries the active site of γ-secretase and is a founding member of a novel class of polytopic aspartyl proteases that utilize a non-classical active site to cleave their membrane-tethered substrates. The other components are required for assembly, stabilization and maturation of the complex and NCT may be involved in the recognition of γ-secretase substrates.
Keywords: alzheimer's disease, amyloid peptide, aph-1, nicastrin, pen-2, presenilin, secretase, secretase complex
Current Alzheimer Research
Title: Uncovering γ-Secretase
Volume: 1 Issue: 3
Author(s): Harald Steiner
Affiliation:
Keywords: alzheimer's disease, amyloid peptide, aph-1, nicastrin, pen-2, presenilin, secretase, secretase complex
Abstract: Accumulation of the amyloid β-peptide (Aβ) in the brain is believed to initiate a series of neurotoxic events that causes neurodegeneration in Alzheimer´s disease (AD). Aβ is generated by processing of the β-amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, β-secretase and γ-secretase. While β-secretase has been identified as the membrane-bound aspartyl protease BACE, the identity of γ-secretase, which catalyzes the final, intramembrane cleavage of APP as well as of several other type I transmembrane proteins, has been enigmatic for a long time. Exciting progress has been made in the past year towards its uncovering. Genetics paved the way for subsequent biochemical reconstitution studies that demonstrated that γ-secretase is a protein complex composed of presenilin (PS), nicastrin (NCT), APH-1 and PEN-2. Thus, the complete set of genes that is required to generate Aβ from its precursor has now ultimately been identified. PS carries the active site of γ-secretase and is a founding member of a novel class of polytopic aspartyl proteases that utilize a non-classical active site to cleave their membrane-tethered substrates. The other components are required for assembly, stabilization and maturation of the complex and NCT may be involved in the recognition of γ-secretase substrates.
Export Options
About this article
Cite this article as:
Steiner Harald, Uncovering γ-Secretase, Current Alzheimer Research 2004; 1 (3) . https://dx.doi.org/10.2174/1567205043332081
DOI https://dx.doi.org/10.2174/1567205043332081 |
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
-
Dynamic Simulation, Docking and DFT Studies Applied to a Set of Anti-Acetylcholinesterase Inhibitors in the enzyme β-Secretase (BACE-1): An Important Therapeutic Target in Alzheimer's Disease
Current Computer-Aided Drug Design Hematopoietic Stem Cells Therapies
Current Stem Cell Research & Therapy Pharmacological Interventions for Binge Eating: Lessons from Animal Models, Current Treatments, and Future Directions
Current Pharmaceutical Design Growth Factors and Astrocytes Metabolism: Possible Roles for Platelet Derived Growth Factor
Medicinal Chemistry Alzheimer Biomarkers and Clinical Alzheimer Disease were Not Associated with Increased Cerebrovascular Disease in a Memory Clinic Population
Current Alzheimer Research Nutrition and Growth in Children with Chronic Liver Disease and After Liver Transplantation
Current Nutrition & Food Science The Use of A Psychodynamic Semi-Structured Personality Assessment Interview in School Settings
Adolescent Psychiatry Current Treatments of Muco-Cutaneous Herpes Simplex Virus Infections
Current Medicinal Chemistry - Anti-Infective Agents Alcoholic Hepatitis: Pathogenesis, Diagnosis and Treatment
Reviews on Recent Clinical Trials Synthesis of the Alzheimer Drug Posiphen into its Primary Metabolic Products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their Inhibition of Amyloid Precursor Protein, α -Synuclein Synthesis, Interleukin-1β Release, and Cholinergic Action.
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Signal Transducer and Activator of Transcription 3 Signaling Pathway: A Potential Target in Sarcoma Treatment
Current Enzyme Inhibition Temporal Progression of Kainic Acid Induced Changes in Vascular Laminin Expression in Rat Brain with Neuronal and Glial Correlates
Current Neurovascular Research Functionalized magnetic nanoparticles for biomedical applications
Current Pharmaceutical Design P2X1 and P2X2 Receptors in the Central Nervous System as Possible Drug Targets
CNS & Neurological Disorders - Drug Targets Homology Modeling of Human Kynurenine Aminotransferase III and Observations on Inhibitor Binding Using Molecular Docking
Central Nervous System Agents in Medicinal Chemistry Regenerative Dendritic Spikes and Synaptic Plasticity
Current Neurovascular Research Editorial [Hot Topic:New Approaches for the Treatment of Pain and Inflammation (Guest Editor: Kaustav Biswas)]
Current Topics in Medicinal Chemistry DNA Minor Groove Binders: an Overview on Molecular Modeling and QSAR Approaches
Current Medicinal Chemistry Recent Patents on Active Self-Ligating Brackets for Orthodontic Treatment
Recent Patents on Mechanical Engineering Pharmacologic Role of Vitamin D Natural Products
Current Vascular Pharmacology