Abstract
The two classical pathological hallmarks of Alzheimers disease are deposits of aggregated β-amyloid (Aβ ) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Aβ pathology, an invariant trait of Alzheimers disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and selfaggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimers disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH2- terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA / cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimers disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.
Keywords: Tau, MAPT, Alzheimer's disease, microtubule, kinase, Cdk, GSK, MARK
Current Topics in Medicinal Chemistry
Title: Tau Therapeutic Strategies for the Treatment of Alzheimers Disease
Volume: 6 Issue: 6
Author(s): Ian Churcher
Affiliation:
Keywords: Tau, MAPT, Alzheimer's disease, microtubule, kinase, Cdk, GSK, MARK
Abstract: The two classical pathological hallmarks of Alzheimers disease are deposits of aggregated β-amyloid (Aβ ) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Aβ pathology, an invariant trait of Alzheimers disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and selfaggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimers disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH2- terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA / cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimers disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.
Export Options
About this article
Cite this article as:
Churcher Ian, Tau Therapeutic Strategies for the Treatment of Alzheimers Disease, Current Topics in Medicinal Chemistry 2006; 6 (6) . https://dx.doi.org/10.2174/156802606776743057
DOI https://dx.doi.org/10.2174/156802606776743057 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...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
-
Plant Polyphenols as Neuroprotective Agents in Parkinson’s Disease Targeting Oxidative Stress
Current Drug Targets Effects of Crosstalks Between Sumoylation and Phosphorylation in Normal Cellular Physiology and Human Diseases
Current Molecular Medicine Crocin Protects Against Beta-Amyloid Peptide-Induced Apoptosis in PC12 Cells Via the PI3 K Pathway
Current Molecular Pharmacology Association between <i>Toxoplasma gondii</i> Infection and Headache: A Systematic Review and Meta-Analysis
Infectious Disorders - Drug Targets Modulating the Amyloidogenesis of α-Synuclein
Current Neuropharmacology Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer’s Disease
Current Alzheimer Research New Molecular Avenues in Parkinson ’ s Disease Therapy
Current Topics in Medicinal Chemistry Dissecting the Biological Effects of Isoflurane through the Mechanistic Target of Rapamycin (mTOR) and microRNAs (miRNAs)
Current Neurovascular Research Virgin Olive Oil and Hypertension
Current Vascular Pharmacology Potential Targets for the Development of Novel Antidepressants: Future Perspectives
CNS & Neurological Disorders - Drug Targets Mechanisms of Neuronal Damage and Neuroprotection Underlying Ischemia/Reperfusion Injury after Physical Exercise
Current Drug Targets Accuracy of Telephone-Based Cognitive Screening Tests: Systematic Review and Meta-Analysis
Current Alzheimer Research Natural Animal Models of Neurodegenerative Protein Misfolding Diseases
Current Pharmaceutical Design Currently Available Drugs for the Treatment of Obesity: Sibutramine and Orlistat
Mini-Reviews in Medicinal Chemistry Multiple Roles for Glycogen Synthase Kinase-3 as a Drug Target in Alzheimers Disease
Current Drug Targets Current Status of Carotid Stenting
Current Vascular Pharmacology Effective Inhibition of Foam Cells Formation by Tanshinone IIA in RAW264.7 Macrophages Induced with LDL Isolated from Hypercholesterolemia Patients: A Proteomic Analysis
Current Proteomics Review of Bioinformatics and Theoretical Studies of Acetylcholinesterase Inhibitors
Current Bioinformatics Post-Translational Modifications in Prion Proteins
Current Protein & Peptide Science Editorial [Hot Topic: Auditory Processing Disorder (Guest Editors: Vasiliki Maria Iliadou)]
Current Pediatric Reviews