Abstract
Accumulation of amyloid β-peptides (Aβ) in the brain is believed to contribute to the development of Alzheimer disease (AD). Aβ, a 40-42 amino acid-comprising proteolytical fragment of the amyloid precursor protein (APP), is released from APP by sequential cleavages via β- and γ-secretases. However, the predominant route of APP processing consists of successive cleavages by α- and γ-secretases. Alpha-secretase attacks APP inside the Aβ sequence, and therefore prevents formation of neurotoxic Aβ. After cleavage by α-secretase, the soluble N-terminal domain of APP, which possesses neurotrophic and neuroprotective properties, is released. In AD patients, a decrease in α-secretase processing of APP has been found and therefore, strategies to improve α-secretase activity are obvious. Several years after descriptive reports on α-secretase, the responsible enzymes have been identified to belong to the family of A Disintegrin And Metalloproteinase (ADAM). Three of these membrane-anchored zinc-dependent metalloproteinases, ADAM10 as well as ADAM17 and presumably also ADAM9 display α-secretase activity. Since the individual knock-out of these proteinases in neither case completely prevented α-secretase processing of APP, it seems likely that different ADAMs are compensating mutually, and under different conditions may contribute to α-secretase cleavage of APP. In addition to ADAMs, perhaps other membrane-associated metalloproteinases contribute to the shedding of APP. Stimulation of α-secretase activities can be achieved via several signaling cascades including phospholipase C, phosphatidylinositol 3-kinase and serine/threonine-specific kinases such as protein kinases C, and mitogen activated protein kinases. Direct activation of protein kinase C and stimulation of distinct G protein-coupled receptors are known to increase α-secretase processing of APP. Agonists for M1 muscarinic acetylcholine receptors and serotonin 5-HT4 receptors are currently in clinical trials to test their efficiency in the treatment of AD.
Keywords: Alzheimer disease, α-secretase, ADAM, G protein-coupled receptors
Current Alzheimer Research
Title: A Closer Look at α-Secretase
Volume: 5 Issue: 2
Author(s): Rolf Postina
Affiliation:
Keywords: Alzheimer disease, α-secretase, ADAM, G protein-coupled receptors
Abstract: Accumulation of amyloid β-peptides (Aβ) in the brain is believed to contribute to the development of Alzheimer disease (AD). Aβ, a 40-42 amino acid-comprising proteolytical fragment of the amyloid precursor protein (APP), is released from APP by sequential cleavages via β- and γ-secretases. However, the predominant route of APP processing consists of successive cleavages by α- and γ-secretases. Alpha-secretase attacks APP inside the Aβ sequence, and therefore prevents formation of neurotoxic Aβ. After cleavage by α-secretase, the soluble N-terminal domain of APP, which possesses neurotrophic and neuroprotective properties, is released. In AD patients, a decrease in α-secretase processing of APP has been found and therefore, strategies to improve α-secretase activity are obvious. Several years after descriptive reports on α-secretase, the responsible enzymes have been identified to belong to the family of A Disintegrin And Metalloproteinase (ADAM). Three of these membrane-anchored zinc-dependent metalloproteinases, ADAM10 as well as ADAM17 and presumably also ADAM9 display α-secretase activity. Since the individual knock-out of these proteinases in neither case completely prevented α-secretase processing of APP, it seems likely that different ADAMs are compensating mutually, and under different conditions may contribute to α-secretase cleavage of APP. In addition to ADAMs, perhaps other membrane-associated metalloproteinases contribute to the shedding of APP. Stimulation of α-secretase activities can be achieved via several signaling cascades including phospholipase C, phosphatidylinositol 3-kinase and serine/threonine-specific kinases such as protein kinases C, and mitogen activated protein kinases. Direct activation of protein kinase C and stimulation of distinct G protein-coupled receptors are known to increase α-secretase processing of APP. Agonists for M1 muscarinic acetylcholine receptors and serotonin 5-HT4 receptors are currently in clinical trials to test their efficiency in the treatment of AD.
Export Options
About this article
Cite this article as:
Postina Rolf, A Closer Look at α-Secretase, Current Alzheimer Research 2008; 5 (2) . https://dx.doi.org/10.2174/156720508783954668
DOI https://dx.doi.org/10.2174/156720508783954668 |
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
-
Anti-Inflammatory and Anti-Apoptotic Effects of Levosimendan in Decompensated Heart Failure: A Novel Mechanism of Drug-Induced Improvement in Contractile Performance of the Failing Heart
Current Medicinal Chemistry - Cardiovascular & Hematological Agents Ethyl Pyruvate: A Novel Treatment for Sepsis
Current Drug Targets Biologic Agents in the Treatment of Psoriasis
Recent Patents on Inflammation & Allergy Drug Discovery Are Antipsychotics Useful in the Treatment of Anorexia Nervosa? A Review of the Literature
Current Psychopharmacology New Challenges for ACE-Inhibitors in Vascular Diseases
Drug Design Reviews - Online (Discontinued) Long-Term Multimodal Therapy (Verapamil Associated with Propolis, Blueberry, Vitamin E and Local Diclofenac) on Patients with Peyronie's Disease (Chronic Inflammation of the Tunica Albuginea). Results of a Controlled Study
Inflammation & Allergy - Drug Targets (Discontinued) Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms
Recent Patents on CNS Drug Discovery (Discontinued) Combined Treatment Fkt-Botulinum Toxin Type A (Btx-A) in Patients with Strumpell-Lorrain Disease
Current Pharmaceutical Design Aortic Dissection: A Review of the Pathophysiology, Management and Prospective Advances
Current Cardiology Reviews Vasopressin and Terlipressin in Neonates and Children with Refractory Septic Shock
Current Drug Metabolism A Review of Chemistry and Pharmacology of Piperidine Alkaloids of Pinus and Related Genera
Current Pharmaceutical Biotechnology 30 Years Lost in Anesthesia Theory
Cardiovascular & Hematological Agents in Medicinal Chemistry Cardiovascular Benefit of SGLT2 Inhibitors in the Therapeutics of Diabetes Mellitus: A Close Look beyond the Horizon
Current Drug Targets Biochemical Properties of Peptides Encrypted in Bovine Milk Proteins
Current Medicinal Chemistry Contrast Agents in X-Ray Computed Tomography and Its Applications in Oncology
Anti-Cancer Agents in Medicinal Chemistry A2A Adenosine Receptor and its Modulators: Overview on a Druggable GPCR and on Structure-Activity Relationship Analysis and Binding Requirements of Agonists and Antagonists
Current Pharmaceutical Design Male Pelvic Pain: Beyond Urology and Chronic Prostatitis
Current Rheumatology Reviews Structural Development, Haematological Immunological and Pharmacological Effects of Quinolones
Recent Patents on Anti-Infective Drug Discovery Optical and Multimodal Peptide-Based Probes for In Vivo Molecular Imaging
Anti-Cancer Agents in Medicinal Chemistry Inhibition of Zinc Metallopeptidases in Cardiovascular Disease - From Unity to Trinity, or Duality?
Current Pharmaceutical Design