Abstract
Hyperhomocysteinemia (HHcy) has been recognized as a risk factor for developing Alzheimers disease (AD). However, its underlying molecular mechanisms are still elusive. Here we show that HHcy induces an elevation of amyloid beta (Aβ) levels and deposition, as well as behavioral impairments, in a mouse model of AD-like amyloidosis, the Tg2576 mice. This elevation is not associated with significant change of the steady state levels of the Aβ precursor protein (APP), β- or α-secretase pathways, nor with the Aβ catabolic pathways. By contrast, HHcy significantly reduces glycogen synthase kinase 3 (GSK3) Ser21/9 phosphorylation, but not total GSK3 protein levels. Similar results are obtained in brains homogenates from a genetic mouse model of HHcy. In vitro studies show that homocysteine increases Aβ formation, reduces phosphorylated GSK3 levels, without changes in total APP and its metabolism, and these effects are prevented by selective GSK3 inhibition. Overall, these data support a potential link between GSK3 and the pro-amyloidotic effect of HHcy in vivo and in vitro.
Keywords: Amyloid metabolism, amyloid β, Tg2576 mice, glycogen synthase kinase 3
Current Alzheimer Research
Title: Diet-Induced Hyperhomocysteinemia Increases Amyloid-β Formation and Deposition in a Mouse Model of Alzheimers Disease
Volume: 7 Issue: 2
Author(s): J.-M. Zhuo, G. S. Portugal, W. D. Kruger, H. Wang, T. J. Gould and D. Pratico
Affiliation:
Keywords: Amyloid metabolism, amyloid β, Tg2576 mice, glycogen synthase kinase 3
Abstract: Hyperhomocysteinemia (HHcy) has been recognized as a risk factor for developing Alzheimers disease (AD). However, its underlying molecular mechanisms are still elusive. Here we show that HHcy induces an elevation of amyloid beta (Aβ) levels and deposition, as well as behavioral impairments, in a mouse model of AD-like amyloidosis, the Tg2576 mice. This elevation is not associated with significant change of the steady state levels of the Aβ precursor protein (APP), β- or α-secretase pathways, nor with the Aβ catabolic pathways. By contrast, HHcy significantly reduces glycogen synthase kinase 3 (GSK3) Ser21/9 phosphorylation, but not total GSK3 protein levels. Similar results are obtained in brains homogenates from a genetic mouse model of HHcy. In vitro studies show that homocysteine increases Aβ formation, reduces phosphorylated GSK3 levels, without changes in total APP and its metabolism, and these effects are prevented by selective GSK3 inhibition. Overall, these data support a potential link between GSK3 and the pro-amyloidotic effect of HHcy in vivo and in vitro.
Export Options
About this article
Cite this article as:
Zhuo J.-M., Portugal S. G., Kruger D. W., Wang H., Gould J. T. and Pratico D., Diet-Induced Hyperhomocysteinemia Increases Amyloid-β Formation and Deposition in a Mouse Model of Alzheimers Disease, Current Alzheimer Research 2010; 7 (2) . https://dx.doi.org/10.2174/156720510790691326
DOI https://dx.doi.org/10.2174/156720510790691326 |
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
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...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
- 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
-
Evaluation of Post-Surgical Cognitive Function and Protein Fingerprints in the Cerebro-Spinal Fluid Utilizing Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass-Spectrometry (SELDI-TOF MS) After Coronary Artery Bypass Grafting: Review of Proteomic Analytic Tools and Introducing a New Syndrome
Current Medicinal Chemistry Cannabinoids as Therapeutic Agents for Ablating Neuroinflammatory Disease
Endocrine, Metabolic & Immune Disorders - Drug Targets Assessment of Acute Coronary Syndromes: Focus on Novel Biomarkers
Current Medicinal Chemistry Inflammatory Biomarkers in AD: Implications for Diagnosis
Current Alzheimer Research Editorial: Thematic Issue-Topic–Diabetic Cardiovascular Disease–An Unmet Medical Need: Emerging Targets and Therapies-Introduction to the Special Issue
Cardiovascular & Hematological Agents in Medicinal Chemistry Current Understanding of Dietary Polyphenols and their Role in Health and Disease
Current Nutrition & Food Science Electrochemical Biosensor for the Detection of Glycated Albumin
Current Alzheimer Research Omega-3 Polyunsaturated Fatty Acids and Depression: A Review of the Evidence
Current Pharmaceutical Design Network Analysis of Depressive Symptomatology in Elderly Patients with Major Depressive Disorder
Current Psychiatry Research and Reviews Prion Protein Functions and Dysfunction in Prion Diseases
Current Medicinal Chemistry Antihypertensive Therapy: Role of Aldosterone Antagonists
Current Pharmaceutical Design Cognitive Dysfunction in FMR1 Premutation Carriers
Current Psychiatry Reviews Aging is Not a Disorder
Current Aging Science Disentangling the Intricacies of Migraine: A Review
CNS & Neurological Disorders - Drug Targets Alzheimers Disease Drug Development in 2008 and Beyond: Problems and Opportunities
Current Alzheimer Research Alzheimers Disease and P300: Review and Evaluation of Task and Modality
Current Alzheimer Research Patent Selections:
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Endogenous Retroelements in Cellular Senescence and Related Pathogenic Processes: Promising Drug Targets in Age-Related Diseases
Current Drug Targets Magnetic Resonance Imaging of Iron in Parkinsons Disease
Current Medical Imaging Antagonism of Endothelin (ETA and ETB) Receptors During Renovascular Hypertension-Induced Vascular Dementia Improves Cognition
Current Neurovascular Research