Abstract
Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are sporadic and genetic neurodegenerative conditions characterized by brain accumulation and deposition of protein aggregates. In AD, the key pathogenic event is linked to the formation of a 4-kDa amyloid β (Aβ) peptide, generated by sequential cleavages of the amyloid precursor protein (APP). In CJD and other prion diseases, the process is initiated by conformational changes of the cellular prion protein, or PrPC, into a β-sheet rich isoform, named PrPsc, which acquires protease-resistance and detergent insolubility. Once generated, Aβ and PrPsc are highly prone to misassembly under thermodynamically favourable oligomeric forms and protofibril/fibril structures. The variety of physicochemical states exhibited by Aβ and PrPsc is accounted for by distinct molecular forms with different amino and/or carboxyl termini and alternative conformations. Unlike Aβ, PrPsc is also infectious, and this feature poses public health concerns, as in the case of iatrogenic and variant CJD (vCJD). Several lines of evidence suggest that Aβ and PrPsc are the main factors responsible for death of selected neuronal populations in brains of AD and prion diseases victims. Therefore, in addition to symptomatic treatment of dementia, therapeutic efforts are currently aimed at testing the efficacy of disease-modifying, anti-amyloid therapies. Experimental and clinical therapeutic interventions include passive and active immunization against amyloidogenic peptides, non immunological strategies, as well as drugs enhancing the nonamyloidogenic protein processing. In this review, we focus on molecular mechanisms of AD and prion diseases, and on novel treatment approaches.
Keywords: Alzheimer disease, prion diseases, transmissible spongiform encephalopathies, Creutzfeldt-Jakob disease, amyloid precursor protein, dementia, anti-amyloid therapies, protein-misfolding diseases
Current Medicinal Chemistry
Title: Cerebral Amyloidoses: Molecular Pathways and Therapeutic Challenges
Volume: 13 Issue: 16
Author(s): Salvatore Monaco, Gianluigi Zanusso, Sara Mazzucco and Nicola Rizzuto
Affiliation:
Keywords: Alzheimer disease, prion diseases, transmissible spongiform encephalopathies, Creutzfeldt-Jakob disease, amyloid precursor protein, dementia, anti-amyloid therapies, protein-misfolding diseases
Abstract: Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are sporadic and genetic neurodegenerative conditions characterized by brain accumulation and deposition of protein aggregates. In AD, the key pathogenic event is linked to the formation of a 4-kDa amyloid β (Aβ) peptide, generated by sequential cleavages of the amyloid precursor protein (APP). In CJD and other prion diseases, the process is initiated by conformational changes of the cellular prion protein, or PrPC, into a β-sheet rich isoform, named PrPsc, which acquires protease-resistance and detergent insolubility. Once generated, Aβ and PrPsc are highly prone to misassembly under thermodynamically favourable oligomeric forms and protofibril/fibril structures. The variety of physicochemical states exhibited by Aβ and PrPsc is accounted for by distinct molecular forms with different amino and/or carboxyl termini and alternative conformations. Unlike Aβ, PrPsc is also infectious, and this feature poses public health concerns, as in the case of iatrogenic and variant CJD (vCJD). Several lines of evidence suggest that Aβ and PrPsc are the main factors responsible for death of selected neuronal populations in brains of AD and prion diseases victims. Therefore, in addition to symptomatic treatment of dementia, therapeutic efforts are currently aimed at testing the efficacy of disease-modifying, anti-amyloid therapies. Experimental and clinical therapeutic interventions include passive and active immunization against amyloidogenic peptides, non immunological strategies, as well as drugs enhancing the nonamyloidogenic protein processing. In this review, we focus on molecular mechanisms of AD and prion diseases, and on novel treatment approaches.
Export Options
About this article
Cite this article as:
Monaco Salvatore, Zanusso Gianluigi, Mazzucco Sara and Rizzuto Nicola, Cerebral Amyloidoses: Molecular Pathways and Therapeutic Challenges, Current Medicinal Chemistry 2006; 13 (16) . https://dx.doi.org/10.2174/092986706777585022
DOI https://dx.doi.org/10.2174/092986706777585022 |
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
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...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
- 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
-
GSK3 Inhibitors in the Therapeutic Development of Diabetes, Cancer and Neurodegeneration: Past, Present and Future
Current Pharmaceutical Design The Effects of Prostaglandin E-1 in Patients with Intermittent Claudication
Cardiovascular & Hematological Disorders-Drug Targets The Role of the Catechol-o-Methyltransferase (COMT) GeneVal158Met in Aggressive Behavior, a Review of Genetic Studies
Current Neuropharmacology A Comprehensive Study of Pharmacological Behaviors, Nano-Formulations, and Applications of Rosemary
The Natural Products Journal Early Ischemic Blood Brain Barrier Damage: A Potential Indicator for Hemorrhagic Transformation Following Tissue Plasminogen Activator (tPA) Thrombolysis?
Current Neurovascular Research Informal Caregiving for People with Dementia and Women’s Health: A Gender-based Assessment of Studies on Resilience
Current Women`s Health Reviews Treatment and Prevention of Alcohol Hangover
Current Drug Abuse Reviews Platelets in Rheumatic Diseases: Friend or Foe?
Current Pharmaceutical Design Genetic Algorithm and Self-Organizing Maps for QSPR Study of Some N-aryl Derivatives as Butyrylcholinesterase Inhibitors
Current Drug Discovery Technologies Syntheses and In-Vitro Evaluation of Novel Adamantane Based γ-Secretase Inhibitors
Current Medicinal Chemistry "Take and Run" and "Take and Hold" Therapeutical Electromagnetic Field Application Modalities in Physiotherapy: Some Clinically Significant Pathways of Action
Current Chemical Biology Is Alpha-Synuclein Pathology a Target for Treatment of Neurodegenerative Disorders?
Current Alzheimer Research Vitamins in the Prevention or Delay of Cognitive Disability of Aging
Current Aging Science In Vitro Models of the Blood-Brain Barrier: When to Use Which?
Current Medicinal Chemistry - Central Nervous System Agents Coffee: A Rich Source of Antimicrobial and Antiviral Compounds
Clinical Immunology, Endocrine & Metabolic Drugs (Discontinued) A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of Safety and Tolerability of Two Doses of Divalproex Sodium in Outpatients with Probable Alzheimers Disease
Current Alzheimer Research Anti-Amyloid Treatments in Alzheimers Disease
Recent Patents on CNS Drug Discovery (Discontinued) Pharmacogenomics in Psychiatry: Implications for Practice
Recent Patents on Biotechnology Histamine H4 Receptor: A Novel Target for Inflammation Therapy
Mini-Reviews in Medicinal Chemistry Prostaglandins and Cyclooxygenases in Glial Cells During Brain Inflammation
Current Drug Targets - Inflammation & Allergy