Abstract
The accumulation of amyloid β peptide (Aβ) is believed to be an early and critical event leading to synapse and neuronal cell loss in Alzheimers Disease (AD). Aβ itself is toxic to neurons in vitro and the load of Aβ in vivo causes the loss of synapses and neurons in brain in animal models. Therefore, there has been considerable interest in elucidating the mechanism(s) of Aβ neurotoxicity. Here, we review the molecular signaling pathways involved in Aβ-induced cell death, including signaling through the neuronal nicotinic receptor and the Aβ-triggered generation of reactive oxygen species (ROS) leading to the activation of the c-jun N-terminal kinase (JNK), and the ensuing phosphorylation of p66Shc and inactivation of the Forkhead transcription factors. This focused review not only provides a better understanding of the signaling mechanisms involved in Aβ-induced cell death, but also underscores the potential of JNK, p66Shc, Forkhead proteins, p25/cdk5, and neuronal nicotinic receptor, as therapeutic targets for AD.
Keywords: JNK, p66Shc, Forkhead proteins, cdk5, apoptosis, phosphorylation, reactive oxygen species, neuronal nicotinic receptor
CNS & Neurological Disorders - Drug Targets
Title: Signaling Mechanisms Underlying Aβ Toxicity: Potential Therapeutic Targets for Alzheimers Disease
Volume: 5 Issue: 3
Author(s): Wanli W. Smith, Myriam Gorospe and John W. Kusiak
Affiliation:
Keywords: JNK, p66Shc, Forkhead proteins, cdk5, apoptosis, phosphorylation, reactive oxygen species, neuronal nicotinic receptor
Abstract: The accumulation of amyloid β peptide (Aβ) is believed to be an early and critical event leading to synapse and neuronal cell loss in Alzheimers Disease (AD). Aβ itself is toxic to neurons in vitro and the load of Aβ in vivo causes the loss of synapses and neurons in brain in animal models. Therefore, there has been considerable interest in elucidating the mechanism(s) of Aβ neurotoxicity. Here, we review the molecular signaling pathways involved in Aβ-induced cell death, including signaling through the neuronal nicotinic receptor and the Aβ-triggered generation of reactive oxygen species (ROS) leading to the activation of the c-jun N-terminal kinase (JNK), and the ensuing phosphorylation of p66Shc and inactivation of the Forkhead transcription factors. This focused review not only provides a better understanding of the signaling mechanisms involved in Aβ-induced cell death, but also underscores the potential of JNK, p66Shc, Forkhead proteins, p25/cdk5, and neuronal nicotinic receptor, as therapeutic targets for AD.
Export Options
About this article
Cite this article as:
Smith W. Wanli, Gorospe Myriam and Kusiak W. John, Signaling Mechanisms Underlying Aβ Toxicity: Potential Therapeutic Targets for Alzheimers Disease, CNS & Neurological Disorders - Drug Targets 2006; 5 (3) . https://dx.doi.org/10.2174/187152706784111515
DOI https://dx.doi.org/10.2174/187152706784111515 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...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
Related Articles
-
Immunology Behind Tumors: A Mini Review
Current Cancer Therapy Reviews Chemotherapy In Japanese Encephalitis: Are We There Yet?
Infectious Disorders - Drug Targets Targeting the Alpha 7 Nicotinic Acetylcholine Receptor to Reduce Amyloid Accumulation in Alzheimers Disease Pyramidal Neurons
Current Pharmaceutical Design Opiate Drug Use and the Pathophysiology of NeuroAIDS
Current HIV Research Cannabinoid System as a Potential Target for Drug Development in the Treatment of Cardiovascular Disease
Current Vascular Pharmacology Medicinal Value and Potential Therapeutic Mechanisms of Gynostemma pentaphyllum (Thunb.) Makino and Its Derivatives: An Overview
Current Topics in Medicinal Chemistry Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates
Current Topics in Medicinal Chemistry Nitric Oxide Control of Proliferation in Nerve Cells and in Tumor Cells of Nervous Origin
Current Pharmaceutical Design Peripheral Benzodiazepine Receptor (PBR) New Insight in Cell Proliferation and Cell Differentiation Review
Current Clinical Pharmacology Effects of Tobacco Nicotine-Derived Nitrosamine Ketone (NNK) Exposures on Brain Alcohol Metabolizing Enzyme Activities
Drug Metabolism Letters Voltage-Gated Calcium Channels as Targets for the Treatment of Chronic Pain
Current Drug Targets - CNS & Neurological Disorders Microalgal Fatty Acids and Their Implication in Health and Disease
Mini-Reviews in Medicinal Chemistry The Potential Use of Hormone-Based Therapeutics for the Treatment of Alzheimers Disease
Current Alzheimer Research Targeted Tumor Diagnosis and Therapy with Peptide Hormones as Radiopharmaceuticals
Anti-Cancer Agents in Medicinal Chemistry The Stress Rheostat: An Interplay Between the Unfolded Protein Response (UPR) and Autophagy in Neurodegeneration
Current Molecular Medicine Mechanism of Cancer Drug Resistance and the Involvement of Noncoding RNAs
Current Medicinal Chemistry Mechanisms of Acupuncture Effect on Alzheimer’s Disease in Animal- Based Researches
Current Topics in Medicinal Chemistry Cancer Immunotherapy: Battling Tumors with Gene Vaccines
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects
Current Alzheimer Research A hypothesis for the role of RECK in angiogenesis
Current Vascular Pharmacology