Abstract
Alzheimers disease (AD) is a complex disease, involving multiple factors such as the production of aggregation- prone amyloid β (Aβ) peptides, the formation of fibrillarly tangles of microtubule-associating proteins, Tau, and the polymorphism of cholesterol binding protein, APOE4. While understanding the mechanism of AD and the involvement of key players should lead to rational drug discovery against this disease, a traditional screening approach should also work for identifying drugs using AD models. We have used a cellular AD model, in which a cell death was induced by ADcausing neurotoxicities, and then screened the genes, which rescued the cells from the cell death. This resulted in isolation of a gene encoding a novel 24-amino acid long peptide, termed Humanin (HN), which protected neuronal cells at ∼μM level. Surprisingly, these gene products and the synthetic peptides not only protected neurons from cell death induced by Aβ-related neurotoxicities, but also Aβ-unrelated neurotoxicities. While a broad range of activities of HN against ADrelated insults is discovered, the detailed mechanism of its action is still obscure. Structure analysis of HN showed that it is largely disordered and flexible at low peptide concentrations and heavily aggregates at high concentrations. Interestingly, one of the HN analogs, which is 10000-times more active than the parent HN molecule (i.e. active below nM range), was found to be monomeric. Based on findings of structural analyses, we propose here that membrane environment may enable HN to achieve high affinity for target protein(s) with multiple-transmembrane domains, such as G-protein coupled receptors.
Keywords: Alzheimer's disease, Humanin, Neuroprotection, Structure and Function, Circular Dichroism, Sedimentation Analysis, Colivelin, ADNF
Current Medicinal Chemistry
Title: A Rescue Factor for Alzheimers Diseases: Discovery, Activity, Structure,and Mechanism
Volume: 15 Issue: 21
Author(s): T. Arakawa, Y. Kita and T. Niikura
Affiliation:
Keywords: Alzheimer's disease, Humanin, Neuroprotection, Structure and Function, Circular Dichroism, Sedimentation Analysis, Colivelin, ADNF
Abstract: Alzheimers disease (AD) is a complex disease, involving multiple factors such as the production of aggregation- prone amyloid β (Aβ) peptides, the formation of fibrillarly tangles of microtubule-associating proteins, Tau, and the polymorphism of cholesterol binding protein, APOE4. While understanding the mechanism of AD and the involvement of key players should lead to rational drug discovery against this disease, a traditional screening approach should also work for identifying drugs using AD models. We have used a cellular AD model, in which a cell death was induced by ADcausing neurotoxicities, and then screened the genes, which rescued the cells from the cell death. This resulted in isolation of a gene encoding a novel 24-amino acid long peptide, termed Humanin (HN), which protected neuronal cells at ∼μM level. Surprisingly, these gene products and the synthetic peptides not only protected neurons from cell death induced by Aβ-related neurotoxicities, but also Aβ-unrelated neurotoxicities. While a broad range of activities of HN against ADrelated insults is discovered, the detailed mechanism of its action is still obscure. Structure analysis of HN showed that it is largely disordered and flexible at low peptide concentrations and heavily aggregates at high concentrations. Interestingly, one of the HN analogs, which is 10000-times more active than the parent HN molecule (i.e. active below nM range), was found to be monomeric. Based on findings of structural analyses, we propose here that membrane environment may enable HN to achieve high affinity for target protein(s) with multiple-transmembrane domains, such as G-protein coupled receptors.
Export Options
About this article
Cite this article as:
Arakawa T., Kita Y. and Niikura T., A Rescue Factor for Alzheimers Diseases: Discovery, Activity, Structure,and Mechanism, Current Medicinal Chemistry 2008; 15 (21) . https://dx.doi.org/10.2174/092986708785747616
DOI https://dx.doi.org/10.2174/092986708785747616 |
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
-
Developments on Drug Delivery Systems for the Treatment of Mycobacterial Infections
Current Topics in Medicinal Chemistry Targeting Transcription Factors in Acute Leukemia in Children
Current Drug Targets Retraction Notice: Current Management of Vomiting After Tonsillectomy in Children
Current Drug Safety Therapeutic Implications of Tocilizumab, A Humanized Anti-Interleukin-6 Receptor Antibody, for Various Immune-Mediated Diseases: An Update Review
Current Rheumatology Reviews Mechanisms of Hormonal Regulation of Sertoli Cell Development and Proliferation: A Key Process for Spermatogenesis
Current Molecular Pharmacology Articulating A Rights-Based Approach to HIV Treatment and Prevention Interventions
Current HIV Research Pharmacogenomics: The Influence of Genomic Variation on Drug Response
Current Topics in Medicinal Chemistry Economic Evaluation in Paediatric Practice: Examples from Cardiac Critical Care
Current Pediatric Reviews Structural and Functional Organization of miRNAs
Current Pharmacogenomics A Review of Nutrition Education: Before, Between and Beyond Pregnancy
Current Women`s Health Reviews Fundamental Concepts of the Angiogenic Process
Current Molecular Medicine Treatment of Choroidal Neovascularization in High Myopia
Current Drug Targets The Exploitation of Toll-like Receptor 3 Signaling in Cancer Therapy
Current Pharmaceutical Design Editorial (Hot Topic: Neural Stem Cells and Neurodegeneration)
CNS & Neurological Disorders - Drug Targets Drug Abuse, Brain Calcification and Glutamate-Induced Neurodegeneration
Current Drug Abuse Reviews Two Age-Related Accumulation Profiles of Toxic Metals
Current Aging Science Decreased Parathyroid Hormone Levels Despite Persistent Hypocalcemia in Patients with Kidney Failure Recovering from Septic Shock
Endocrine, Metabolic & Immune Disorders - Drug Targets Clinically Relevant Genetic Variations in Drug Metabolizing Enzymes
Current Drug Metabolism Design of Lipophilic Prodrugs to Improve Drug Delivery and Efficacy
Current Drug Targets Current View on the Mechanism of Action of Perifosine in Cancer
Anti-Cancer Agents in Medicinal Chemistry