Abstract
Amyloid beta (Aβ) is the main component of one of the major pathological hallmarks of Alzheimers disease and is generally considered as one of the earliest factors that induce the pathogenic cascade. Aβ is produced from a larger precursor protein through proteolytic cleavage by secretase activities, which results in fragments that differ in size depending on the cleavage site used to create the C-terminus. In addition, heterogeneity at the N-terminus is created by proteases/ peptidases. Moreover, various amino acid modifications further enhance the heterogeneity of Aβ that accumulates in Alzheimer brain. All these species with their different N-and with or without modifications have different aggregation properties. Aβ requires an aggregated state to be pathogenic and the exact aggregation state is a major determinant of the cellular effects of Aβ: smaller oligomeric aggregates are more neurotoxic, whereas large fibrillar aggregates are generally more associated with a glial response. It is therefore increasingly clear that Aβ is not a single entity, but a peptide with multiple molecular appearances. In this review we will discuss the mechanisms leading to the generation of the different Aβ species and their involvement in Alzheimer pathogenesis. This will be discussed in the framework of therapeutic approaches that target one of the steps in the biogenesis of toxic Aβ species: inhibition of the formation of Aβ, inhibition of aggregation and stimulation of its degradation or clearance.
Keywords: Alzheimer's disease, β-amyloid, aggregation, secretase, amino acid modification, proteolysis, therapy
Current Medicinal Chemistry
Title: From Alpha to Omega with Aβ: Targeting the Multiple Molecular Appearances of the Pathogenic Peptide in Alzheimers Disease
Volume: 17 Issue: 3
Author(s): L. De Kimpe and W. Scheper
Affiliation:
Keywords: Alzheimer's disease, β-amyloid, aggregation, secretase, amino acid modification, proteolysis, therapy
Abstract: Amyloid beta (Aβ) is the main component of one of the major pathological hallmarks of Alzheimers disease and is generally considered as one of the earliest factors that induce the pathogenic cascade. Aβ is produced from a larger precursor protein through proteolytic cleavage by secretase activities, which results in fragments that differ in size depending on the cleavage site used to create the C-terminus. In addition, heterogeneity at the N-terminus is created by proteases/ peptidases. Moreover, various amino acid modifications further enhance the heterogeneity of Aβ that accumulates in Alzheimer brain. All these species with their different N-and with or without modifications have different aggregation properties. Aβ requires an aggregated state to be pathogenic and the exact aggregation state is a major determinant of the cellular effects of Aβ: smaller oligomeric aggregates are more neurotoxic, whereas large fibrillar aggregates are generally more associated with a glial response. It is therefore increasingly clear that Aβ is not a single entity, but a peptide with multiple molecular appearances. In this review we will discuss the mechanisms leading to the generation of the different Aβ species and their involvement in Alzheimer pathogenesis. This will be discussed in the framework of therapeutic approaches that target one of the steps in the biogenesis of toxic Aβ species: inhibition of the formation of Aβ, inhibition of aggregation and stimulation of its degradation or clearance.
Export Options
About this article
Cite this article as:
De Kimpe L. and Scheper W., From Alpha to Omega with Aβ: Targeting the Multiple Molecular Appearances of the Pathogenic Peptide in Alzheimers Disease, Current Medicinal Chemistry 2010; 17 (3) . https://dx.doi.org/10.2174/092986710790149765
DOI https://dx.doi.org/10.2174/092986710790149765 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Challenges with Mosquito-borne Viral Diseases: Outbreak of the Monsters
Current Topics in Medicinal Chemistry Tofacitinib-induced Ramsay- Hunt Syndrome in a Patient with Rheumatoid Arthritis
Current Drug Safety Mechanisms of Neuronal Injury and Death in HIV-1 Associated Dementia
Current HIV Research Leptinaemia and Antiendothelial Antibodies in Accelerated Atherosclerosis – Is There a Relationship?
Vascular Disease Prevention (Discontinued) Larvicidal Activity and Click Synthesis of 2-Alkoxyl-2-(1,2,3-Triazole-1- yl)Acetamide Library
Combinatorial Chemistry & High Throughput Screening Endocannabinoids in Neuroimmunology and Stress
Current Drug Targets - CNS & Neurological Disorders Pharmacological Modulation of Th17
Recent Patents on Inflammation & Allergy Drug Discovery Management of COVID-19 very Elderly Patients in Nursing Homes and Long-Term Care Facilities: Description of a New Model and Experience in a Medicalized Nursing Home
Coronaviruses Predicting the Potential Public Health Impact of Disease-Modifying HIV Vaccines in South Africa: The Problem of Subtypes
Current Drug Targets - Infectious Disorders A Clinical Perspective: Anti Taus Treatment in Alzheimers Disease
Current Alzheimer Research Microglia:Neuroprotective and Neurotrophic Cells in the Central Nervous System
Current Drug Targets - Cardiovascular & Hematological Disorders Is Helicobacter pylori the Infectious Trigger for Headache?: A Review
Infectious Disorders - Drug Targets Monocyte and Macrophage Dysfunction as a Cause of HIV-1 Induced Dysfunction of Innate Immunity
Current Molecular Medicine Collateral Damage: Contribution of Peripheral Inflammation to Neurodegenerative Diseases
Current Topics in Medicinal Chemistry Inflammatory Process as a Determinant Factor for the Degeneration of Substantia Nigra Dopaminergic Neurons: Possible Relevance to the Etiology of Parkinsons Disease
Current Medicinal Chemistry - Central Nervous System Agents Structure Function Analysis of West Nile Virus RNA Dependent RNA Polymerase: Molecular Model and Implications for Drug Design
Medicinal Chemistry Combat Military Personnel and Selective Risk Factors for the Development of Dementias - A Review
Current Psychiatry Research and Reviews Vaccine Safety Monitoring Systems in Developing Countries: An Example of the Vietnam Model
Current Drug Safety Emerging Therapies in Relapsing-Remitting Multiple Sclerosis
Reviews on Recent Clinical Trials An Association of Virus Infection with Type 2 Diabetes and Alzheimer’s Disease
CNS & Neurological Disorders - Drug Targets