Abstract
Although there is still no known effective preventative treatment or cure for Alzheimers disease (AD), the development of new drugs that target pathological features that appear early in the course of this disease and alleviate some of the early cognitive and memory symptoms is a laudable goal that may be one step closer. To date, the acetylcholinesterase inhibitors have been the most widely used AD drugs and have been somewhat successful in slowing loss of cognition. In the last few years, a number of studies have demonstrated that amyloid beta (1-42) (Aβ42), the predominant Aβ peptide species in amyloid plaques, first accumulates in vulnerable neurons prior to plaque formation. Recently, we have shown that many (if not most) amyloid plaques in the entorhinal cortex of AD brains are actually the lysis remnants of degenerated, Aβ42-overburdened neurons. Furthermore, the most vulnerable neurons appear to be those that abundantly express the alpha7 nicotinic acetylcholine receptor (α7nAChR), and internalization of Aβ42 appears to be facilitated by the high-affinity binding of Aβ42 to the α7nAChR on neuronal cell surfaces, followed by endocytosis of the resulting complex and its accumulation within the lysosomal compartment. This mechanism provides a reasonable explanation for the selective vulnerability of cholinergic and cholinoceptive neurons in AD brains and for the fact that Aβ42 is the dominant Aβ peptide species in both intraneuronal accumulations and amyloid plaques. In view of the pathophysiological consequences of Aβ42 binding to α7nAChR on neuronal surfaces that stem from excessive intraneuronal Aβ42 accumulation, the α7nAChR could be an important therapeutic target for treatment of AD. In addition, it further emphasizes the potential merits of new and effective therapeutic strategies pointed towards the goal of lowering of Aβ42 levels in the blood and cerebrospinal fluid as well as blocking Aβ42 in the blood from penetrating the blood-brain barrier and entering into the brain parenchyma.
Current Pharmaceutical Design
Title: Targeting the Alpha 7 Nicotinic Acetylcholine Receptor to Reduce Amyloid Accumulation in Alzheimers Disease Pyramidal Neurons
Volume: 12 Issue: 6
Author(s): Michael R. D`Andrea and Robert G. Nagele
Affiliation:
Abstract: Although there is still no known effective preventative treatment or cure for Alzheimers disease (AD), the development of new drugs that target pathological features that appear early in the course of this disease and alleviate some of the early cognitive and memory symptoms is a laudable goal that may be one step closer. To date, the acetylcholinesterase inhibitors have been the most widely used AD drugs and have been somewhat successful in slowing loss of cognition. In the last few years, a number of studies have demonstrated that amyloid beta (1-42) (Aβ42), the predominant Aβ peptide species in amyloid plaques, first accumulates in vulnerable neurons prior to plaque formation. Recently, we have shown that many (if not most) amyloid plaques in the entorhinal cortex of AD brains are actually the lysis remnants of degenerated, Aβ42-overburdened neurons. Furthermore, the most vulnerable neurons appear to be those that abundantly express the alpha7 nicotinic acetylcholine receptor (α7nAChR), and internalization of Aβ42 appears to be facilitated by the high-affinity binding of Aβ42 to the α7nAChR on neuronal cell surfaces, followed by endocytosis of the resulting complex and its accumulation within the lysosomal compartment. This mechanism provides a reasonable explanation for the selective vulnerability of cholinergic and cholinoceptive neurons in AD brains and for the fact that Aβ42 is the dominant Aβ peptide species in both intraneuronal accumulations and amyloid plaques. In view of the pathophysiological consequences of Aβ42 binding to α7nAChR on neuronal surfaces that stem from excessive intraneuronal Aβ42 accumulation, the α7nAChR could be an important therapeutic target for treatment of AD. In addition, it further emphasizes the potential merits of new and effective therapeutic strategies pointed towards the goal of lowering of Aβ42 levels in the blood and cerebrospinal fluid as well as blocking Aβ42 in the blood from penetrating the blood-brain barrier and entering into the brain parenchyma.
Export Options
About this article
Cite this article as:
D`Andrea Michael R. and Nagele G. Robert, Targeting the Alpha 7 Nicotinic Acetylcholine Receptor to Reduce Amyloid Accumulation in Alzheimers Disease Pyramidal Neurons, Current Pharmaceutical Design 2006; 12 (6) . https://dx.doi.org/10.2174/138161206775474224
DOI https://dx.doi.org/10.2174/138161206775474224 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Betulinic Acid as a Potent and Complex Antitumor Phytochemical: A Minireview
Anti-Cancer Agents in Medicinal Chemistry Exosomes: The Messengers of Health and Disease
Current Neuropharmacology Recent Advances in Cancer Therapy: An Overview
Current Pharmaceutical Design Chinese Herbs and Herbal Extracts for Neuroprotection of Dopaminergic Neurons and Potential Therapeutic Treatment of Parkinson’s Disease
CNS & Neurological Disorders - Drug Targets “SLY AS A FOXO”: New Paths with Forkhead Signaling in the Brain
Current Neurovascular Research Induction of Tumour Cell Senescence: A New Strategy in Anticancer Treatment
Medicinal Chemistry Reviews - Online (Discontinued) Inflammatory Mechanisms and Oxidative Stress as Key Factors Responsible for Progression of Neurodegeneration: Role of Brain Innate Immune System
CNS & Neurological Disorders - Drug Targets Differential Effects of Doxazosin on Renin-Angiotensin-System- Regulating Aminopeptidase Activities in Neuroblastoma and Glioma Tumoral Cells
CNS & Neurological Disorders - Drug Targets <i>In Vitro</i> Cytotoxicity and Apoptosis Inducing Evaluation of Novel Halogenated Isatin Derivatives
Anti-Cancer Agents in Medicinal Chemistry T Cell Redirecting Therapies for Cancer Treatment
Current Cancer Drug Targets Mechanism of CNS Drugs and their Combinations for Alzheimers Disease
Central Nervous System Agents in Medicinal Chemistry Involvement of Uridine-Nucleotide-Stimulated P2Y Receptors in Neuronal Growth and Function
Central Nervous System Agents in Medicinal Chemistry Fluorescent Carbon Dots and Nanodiamonds for Biological Imaging: Preparation, Application, Pharmacokinetics and Toxicity
Current Drug Metabolism Some Implications of Receptor Kinase Signaling Pathway for Development of Multitargeted Kinase Inhibitors
Current Radiopharmaceuticals The Association Between Alcohol Use and the Progression of Alzheimer’s Disease
Current Alzheimer Research Evolution of the Strategies for Screening and Identifying Human Tumor Antigens
Current Protein & Peptide Science Gynecomastia in Infants, Children, and Adolescents
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery The Role of Tau Phosphorylation in the Pathogenesis of Alzheimers Disease
Current Alzheimer Research Mitophagy in Carcinogenesis and Tumour Progression- A New Paradigm with Emerging Importance
Anti-Cancer Agents in Medicinal Chemistry Targeting Indoleamine 2,3-dioxygenase (IDO) to Counteract Tumour- Induced ImmuneDysfunction: From Biochemistry to Clinical Development
Endocrine, Metabolic & Immune Disorders - Drug Targets