Abstract
The M1 muscarinic receptor (M1 mAChR), preserved in Alzheimers disease (AD), is a pivotal target that links major hallmarks of AD, e.g. cholinergic deficiency, cognitive dysfunctions, β-amyloid (Aβ) and tau pathologies. Some muscarinic agonists, while effective in AD, had limited clinical value due to adverse effects and lack of M1 selectivity. The M1 selective muscarinic agonists AF102B [Cevimeline], AF150(S) and AF267B – i) elevated αAPPs, decreased Aβ levels and tau hyperphosphorylation, and blocked Aβ-induced neurotoxicity, in vitro, via M1 mAChR-modulation of kinases (e.g. PKC, MAPK and GSK3β); ii) restored cognitive deficits, cholinergic markers, and decreased tau hyperphosphorylation in relevant models with a wide safety margin. AF267B decreased brain Aβ levels in hypercholesterolemic rabbits and decreased CSF Aβ42 in rabbits and removed vascular Aβ42 deposition from cortex in cholinotoxin-treated rabbits. In 3x transgenic-AD mice that recapitulate the major pathologies and cognitive deficits of AD, chronic AF267B treatment rescued cognitive deficits and decreased Aβ42 and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR-activation of ADAM17/TACE and decreased BACE1 steady state levels and inhibition of GSK3β, extending findings from above. Conclusions: A comprehensive therapy should target all AD hallmarks, regardless of the culprit(s) responsible for the disease. In this context, AF267B is the 1st reported low MW CNS-penetrable mono-therapy that meets this challenge. Clinical trials will determine if AF267B may become an important therapy in AD.
Keywords: Alzheimers disease, mAChR, PKC levels, BACE1 inhibitors, M1 agonists
Current Alzheimer Research
Title: M1 Muscarinic Agonists Target Major Hallmarks of Alzheimers Disease – an Update
Volume: 4 Issue: 5
Author(s): Abraham Fisher
Affiliation:
Keywords: Alzheimers disease, mAChR, PKC levels, BACE1 inhibitors, M1 agonists
Abstract: The M1 muscarinic receptor (M1 mAChR), preserved in Alzheimers disease (AD), is a pivotal target that links major hallmarks of AD, e.g. cholinergic deficiency, cognitive dysfunctions, β-amyloid (Aβ) and tau pathologies. Some muscarinic agonists, while effective in AD, had limited clinical value due to adverse effects and lack of M1 selectivity. The M1 selective muscarinic agonists AF102B [Cevimeline], AF150(S) and AF267B – i) elevated αAPPs, decreased Aβ levels and tau hyperphosphorylation, and blocked Aβ-induced neurotoxicity, in vitro, via M1 mAChR-modulation of kinases (e.g. PKC, MAPK and GSK3β); ii) restored cognitive deficits, cholinergic markers, and decreased tau hyperphosphorylation in relevant models with a wide safety margin. AF267B decreased brain Aβ levels in hypercholesterolemic rabbits and decreased CSF Aβ42 in rabbits and removed vascular Aβ42 deposition from cortex in cholinotoxin-treated rabbits. In 3x transgenic-AD mice that recapitulate the major pathologies and cognitive deficits of AD, chronic AF267B treatment rescued cognitive deficits and decreased Aβ42 and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR-activation of ADAM17/TACE and decreased BACE1 steady state levels and inhibition of GSK3β, extending findings from above. Conclusions: A comprehensive therapy should target all AD hallmarks, regardless of the culprit(s) responsible for the disease. In this context, AF267B is the 1st reported low MW CNS-penetrable mono-therapy that meets this challenge. Clinical trials will determine if AF267B may become an important therapy in AD.
Export Options
About this article
Cite this article as:
Fisher Abraham, M1 Muscarinic Agonists Target Major Hallmarks of Alzheimers Disease – an Update, Current Alzheimer Research 2007; 4 (5) . https://dx.doi.org/10.2174/156720507783018163
DOI https://dx.doi.org/10.2174/156720507783018163 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...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
-
Multiple Mechanisms of Cytokine Action in Neurodegenerative and Psychiatric States: Neurochemical and Molecular Substrates
Current Pharmaceutical Design Novel Risk Factors Related to Stable Angina
Current Pharmaceutical Design State-of-the-Art Methodologies for the Discovery and Characterization of DNA G-Quadruplex Binders
Current Pharmaceutical Design Current Understanding of Central Nervous System Drainage Systems: Implications in the Context of Neurodegenerative Diseases
Current Neuropharmacology Short- and Long-Term Survival of Nonsurgical Intensive Care Patients and its Relation to Diagnosis, Severity of Disease, Age and Comorbidities
Current Aging Science CNS Drug Development – Lost in Translation?
Mini-Reviews in Medicinal Chemistry Inhibitors and Modulators of β- and γ-Secretase
Current Topics in Medicinal Chemistry Cardiac Biomarkers in Stroke, Alzheimer’s Disease, and Other Dementia. Are They of Use? A Brief Overview of Data from Recent Investigations
CNS & Neurological Disorders - Drug Targets Measuring Morphological and Cellular Changes in Alzheimers Dementia: A Review Emphasizing Stereology
Current Alzheimer Research MicroRNAs: Key Players in Microglia and Astrocyte Mediated Inflammation in CNS Pathologies
Current Medicinal Chemistry Opinion Paper: A Cognitive-cultural Segregation and the Three Stages of Aging
Current Aging Science Non-Globular Structures of Tandem Repeats in Proteins
Protein & Peptide Letters Homocysteine and Cerebral Stroke in Developing Countries
Current Medicinal Chemistry Relationship Between Cigarette Smoking and Other Coronary Risk Factors in Atherosclerosis: Risk of Cardiovascular Disease and Preventive Measures
Current Pharmaceutical Design The Novel Multi-Target Iron Chelator, M30 Modulates HIF-1α-Related Glycolytic Genes and Insulin Signaling Pathway in the Frontal Cortex of APP/PS1 Alzheimer’s Disease Mice
Current Alzheimer Research Animal Models of Gastric Bleeding Induced by Dual Antiplatelet Therapy Using Aspirin and Clopidogrel - Prophylactic Effect of Antiulcer Drugs
Current Pharmaceutical Design Locus (Coeruleus) Minoris Resistentiae in Pathogenesis of Alzheimer’s Disease
Current Alzheimer Research Catheter Ablation of Lone Atrial Fibrillation
Current Pharmaceutical Design Statin Treatment and Carotid Plaque Composition: A Review of Clinical Studies
Current Vascular Pharmacology Current Options and Future Possibilities for the Treatment of Dyskinesia and Motor Fluctuations in Parkinson's Disease
CNS & Neurological Disorders - Drug Targets