Abstract
Most drug discovery efforts for Alzheimers disease (AD) have focused on prevention or clearance of β- amyloid (Aβ) fibrils or oligomers, with far less attention to prevention of τ abnormalities that lead to neurofibrillary tangles (NFTs). Much evidence now indicates that Ab multimers can trigger neurodegenerative changes that involve formation of dystrophic neurites and cytoskeletal collapse, possibly due loss of microtubule (MT) stabilization by the τ protein. We have found that several MT-stabilizing agents such as Taxol significantly enhanced neuronal survival in the presence of Aβ and identified agents that enter the brain, a necessity for in vivo testing in animal models of t pathology. Studies were designed to test two agents in the τ mutant (JNPL3) mouse that develops severe motor deficits at about seven months of age, accompanied by neuropathological markers of t pathology. In addition to using motor performance tests through the planned period of drug administration, we designed a simple appetitive memory test that required a reduction in ad lib food intake. Although the neurochemical data are still being analyzed, we were surprised to find that all of the JNPL3 mice, whether receiving the drug or not, developed no signs of motor impairment up to 10 months of age. This is considerably beyond the age at which free-fed mice survived and suggests that the food restriction alone may have delayed the pathological process. A study is ongoing with free-fed mice to determine if the drug interventions do have any beneficial effects in these mutant mice.
Keywords: neurodegeneration, AD-like mouse model, KU-237, JNPL3 mice, microtubule
Current Alzheimer Research
Title: Ongoing In Vivo Studies with Cytoskeletal Drugs in Tau Transgenic Mice
Volume: 3 Issue: 3
Author(s): Mary L. Michaelis
Affiliation:
Keywords: neurodegeneration, AD-like mouse model, KU-237, JNPL3 mice, microtubule
Abstract: Most drug discovery efforts for Alzheimers disease (AD) have focused on prevention or clearance of β- amyloid (Aβ) fibrils or oligomers, with far less attention to prevention of τ abnormalities that lead to neurofibrillary tangles (NFTs). Much evidence now indicates that Ab multimers can trigger neurodegenerative changes that involve formation of dystrophic neurites and cytoskeletal collapse, possibly due loss of microtubule (MT) stabilization by the τ protein. We have found that several MT-stabilizing agents such as Taxol significantly enhanced neuronal survival in the presence of Aβ and identified agents that enter the brain, a necessity for in vivo testing in animal models of t pathology. Studies were designed to test two agents in the τ mutant (JNPL3) mouse that develops severe motor deficits at about seven months of age, accompanied by neuropathological markers of t pathology. In addition to using motor performance tests through the planned period of drug administration, we designed a simple appetitive memory test that required a reduction in ad lib food intake. Although the neurochemical data are still being analyzed, we were surprised to find that all of the JNPL3 mice, whether receiving the drug or not, developed no signs of motor impairment up to 10 months of age. This is considerably beyond the age at which free-fed mice survived and suggests that the food restriction alone may have delayed the pathological process. A study is ongoing with free-fed mice to determine if the drug interventions do have any beneficial effects in these mutant mice.
Export Options
About this article
Cite this article as:
Michaelis L. Mary, Ongoing In Vivo Studies with Cytoskeletal Drugs in Tau Transgenic Mice, Current Alzheimer Research 2006; 3 (3) . https://dx.doi.org/10.2174/156720506777632880
DOI https://dx.doi.org/10.2174/156720506777632880 |
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
-
Establishing Genomic/Transcriptomic Links Between Alzheimer’s Disease and Type 2 Diabetes Mellitus by Meta-Analysis Approach
CNS & Neurological Disorders - Drug Targets Complex Atheromatosis of the Aortic Arch in Cerebral Infarction
Current Cardiology Reviews CDK5 and MAPT Gene Expression in Alzheimer's Disease Brain Samples
Current Alzheimer Research Neurobiology of Bipolar Disorder: Abnormalities on Cognitive and Cortical Functioning and Biomarker Levels
CNS & Neurological Disorders - Drug Targets Relationship of Neurofilament Light (NfL) and Cognitive Performance in a Sample of Mexican Americans with Normal Cognition, Mild Cognitive Impairment and Dementia
Current Alzheimer Research Recent Knowledge on Medicinal Plants as Source of Cholinesterase Inhibitors for the Treatment of Dementia
Mini-Reviews in Medicinal Chemistry Cholinesterase Inhibitors Slow Decline in Executive Functions, Rather than Memory, in Alzheimers Disease: A 1-Year Observational Study in the Sunnybrook Dementia Cohort
Current Alzheimer Research Berberine Ameliorates Cognitive Impairment by Regulating Microglial Polarization and Increasing Expression of Anti-inflammatory Factors following Permanent Bilateral Common Carotid Artery Occlusion in Rats
CNS & Neurological Disorders - Drug Targets Mitochondrial Abnormalities in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer's Disease
Current Alzheimer Research Combining Structural Magnetic Resonance Imaging and Visuospatial Tests to Classify Mild Cognitive Impairment
Current Alzheimer Research PLA2G6 Mutations and Other Rare Causes of Neurodegeneration with Brain Iron Accumulation
Current Drug Targets Planum Temporale Analysis Via a New Volumetric Method in Autoptic Brains of Demented and Psychotic Patients
Current Alzheimer Research Neural Stem Cells Transplanted in a Mouse Model of Parkinson’s Disease Differentiate to Neuronal Phenotypes and Reduce Rotational Deficit
CNS & Neurological Disorders - Drug Targets Nutraceuticals and their Derived Nano-Formulations for the Prevention and Treatment of Alzheimer's Disease
Current Molecular Pharmacology Nerve Growth Factor: Structure, Function and Therapeutic Implications for Alzheimers Disease
Current Drug Targets - CNS & Neurological Disorders Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca<sup>2+</sup> Sensitivity
Current Vascular Pharmacology Genetically-mediated Grey and White Matter Alteration in Normal Elderly Individuals with the CLU-C Allele Gene
Current Alzheimer Research In Vitro and In Vivo Metabolism of a Gamma-Secretase Inhibitor BMS-299897 and Generation of Active Metabolites in Milligram Quantities with a Microbial Bioreactor
Current Drug Metabolism Lipophilic Analogs of Thioflavin S as Novel Amyloid-Imaging Agents
Current Alzheimer Research Biomarkers in Amyotrophic Lateral Sclerosis: Is There A Neurovascular Pathway?
Current Neurovascular Research