Abstract
Objectives: Microglial overactivation, which is secondary to abnormalities of amyloid-beta peptide (Aβ) and tau proteins in the pathogenic cascade leading to onset of Alzheimers disease (AD), accelerates tau pathology, according to our recent observations using mouse models of tauopathies, and this positive feedback results in formation of a vicious cycle between upstream and downstream processes, potentially hampering effective suppression of the entire cascade by anti-amyloid treatments. This motivates our present work aimed at dual monitoring of amyloidosis and microgliosis in living animal models of AD, toward therapeutic regulation of these two processes capable of halting the self-perpetuating cycle. Methods: Transgenic mice expressing mutant amyloid precursor protein (APP23 mice) was examined by highresolution positron emission tomography (PET) after administration of amyloid probe, Pittsburg Compound B (PIB) synthesized with high specific radioactivity (SA). Microglial activation in these mice was also imaged by PET and specific tracer, [18F]fluoroethyl-DAA1106. Results: Progressive amyloidosis in APP23 mice was visualized by PET and high-SA PIB. In vitro assays revealed preferential binding of PIB to N-terminally modified Aβ, AβN3pE. As levels of this Aβ subspecies in model mice are lower than those in AD patients, our findings plausibly explain advantages of high-SA tracers in sensitive detection of mouse amyloid. Near-simultaneous monitoring of amyloid removal and microgliosis in APP23 mice following injection of anti-Aβ antibody demonstrated positive correlation between levels of initially existing amyloid and antibody-induced microglial activation, suggesting the possibility of microglial overactivation in immunotherapy for subjects with abundant amyloid. Conclusions: The present animal imaging system would substantially facilitate establishment of a safe and effective therapeutic strategy targeting multiple key processes in the AD pathogenesis.
Keywords: Amyloid, Aβ, tau, transgenic mouse, positron emission tomography, microglia, imaging biomarker
Current Alzheimer Research
Title: Visualization of Brain Amyloid and Microglial Activation in Mouse Models of Alzheimers Disease
Volume: 6 Issue: 2
Author(s): Makoto Higuchi
Affiliation:
Keywords: Amyloid, Aβ, tau, transgenic mouse, positron emission tomography, microglia, imaging biomarker
Abstract: Objectives: Microglial overactivation, which is secondary to abnormalities of amyloid-beta peptide (Aβ) and tau proteins in the pathogenic cascade leading to onset of Alzheimers disease (AD), accelerates tau pathology, according to our recent observations using mouse models of tauopathies, and this positive feedback results in formation of a vicious cycle between upstream and downstream processes, potentially hampering effective suppression of the entire cascade by anti-amyloid treatments. This motivates our present work aimed at dual monitoring of amyloidosis and microgliosis in living animal models of AD, toward therapeutic regulation of these two processes capable of halting the self-perpetuating cycle. Methods: Transgenic mice expressing mutant amyloid precursor protein (APP23 mice) was examined by highresolution positron emission tomography (PET) after administration of amyloid probe, Pittsburg Compound B (PIB) synthesized with high specific radioactivity (SA). Microglial activation in these mice was also imaged by PET and specific tracer, [18F]fluoroethyl-DAA1106. Results: Progressive amyloidosis in APP23 mice was visualized by PET and high-SA PIB. In vitro assays revealed preferential binding of PIB to N-terminally modified Aβ, AβN3pE. As levels of this Aβ subspecies in model mice are lower than those in AD patients, our findings plausibly explain advantages of high-SA tracers in sensitive detection of mouse amyloid. Near-simultaneous monitoring of amyloid removal and microgliosis in APP23 mice following injection of anti-Aβ antibody demonstrated positive correlation between levels of initially existing amyloid and antibody-induced microglial activation, suggesting the possibility of microglial overactivation in immunotherapy for subjects with abundant amyloid. Conclusions: The present animal imaging system would substantially facilitate establishment of a safe and effective therapeutic strategy targeting multiple key processes in the AD pathogenesis.
Export Options
About this article
Cite this article as:
Higuchi Makoto, Visualization of Brain Amyloid and Microglial Activation in Mouse Models of Alzheimers Disease, Current Alzheimer Research 2009; 6 (2) . https://dx.doi.org/10.2174/156720509787602906
DOI https://dx.doi.org/10.2174/156720509787602906 |
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
-
Models of Change in Schizophrenia: One for All, or All for Some?
Current Psychiatry Reviews Editorial (Thematic Issue: Cell Metabolism and Current Challenges in Drug Research)
Current Pharmaceutical Design Urinary Metabolomics Reveals Alterations of Aromatic Amino Acid Metabolism of Alzheimer’s Disease in the Transgenic CRND8 Mice
Current Alzheimer Research α-Melanocyte Stimulating Hormone as a Potential Therapy for Alzheimer's Disease
Current Alzheimer Research Valproic Acid Attenuates Neuronal Loss in the Brain of APP/PS1 Double Transgenic Alzheimer’s Disease Mice Model
Current Alzheimer Research Transgenic Mouse Models of Parkinsons Disease and Huntingtons Disease
CNS & Neurological Disorders - Drug Targets Platelets: Their Potential Contribution to the Generation of Beta-amyloid Plaques in Alzheimer’s Disease
Current Neurovascular Research Pathogenesis of Alzheimer Disease: Role of Oxidative Stress, Amyloid-β Peptides, Systemic Ammonia and Erythrocyte Energy Metabolism
CNS & Neurological Disorders - Drug Targets Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer's Disease: The NF-κB Connection
Current Topics in Medicinal Chemistry Brain-Skin Connection: Stress, Inflammation and Skin Aging
Inflammation & Allergy - Drug Targets (Discontinued) Ameliorative Effect of Trans-Sinapic Acid and its Protective Role in Cerebral Hypoxia in Aluminium Chloride Induced Dementia of Alzheimer's Type
CNS & Neurological Disorders - Drug Targets Platelet Resistance to Antiplatelet Drugs
Recent Patents on Cardiovascular Drug Discovery Antioxidants Suppress Th1-Type Immune Response In Vitro
Drug Metabolism Letters Targeting Epigenetics in Nervous System Disease
CNS & Neurological Disorders - Drug Targets Neurologic Sequelae in Critical Illness: Evaluation and Outcomes
Current Respiratory Medicine Reviews Editorial [Hot Topic: Cognition Therapeutics (Guest Editor: Miao-Kun Sun)]
Current Drug Targets - CNS & Neurological Disorders Laboratory Techniques for Human Viral Encephalitis Diagnosis
Infectious Disorders - Drug Targets β-Sheet Breakers for Alzheimers Disease Therapy
Current Drug Targets Dietary Patterns and Cognitive Decline: key features for prevention
Current Pharmaceutical Design Astrocytes as an HIV Reservoir: Mechanism of HIV Infection
Current HIV Research