Abstract
In vivo and in vitro studies have shown that gelsolin is an anti-amyloidogenic protein. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the expression of gelsolin. Fibrillized amyoid beta-protein (Aβ) is a key constituent of amyloid plaques in the brains of patients with Alzheimer’s disease (AD). We studied the effects of TSA on the levels of gelsolin; amyloid precursor protein (APP); proteolytic enzymes (γ-secretase and β-secretase) responsible for the production of Aβ; Aβ-cleaving enzymes, i.e., neprilysin (NEP) and insulin-degrading enzyme (IDE); and amyloid load in the double transgenic (Tg) APPswe/PS1δE9 mouse model of AD. Intraperitoneal injection of TSA for two months (9–11 months of age) resulted in decreased activity of HDAC, and increased levels of gelsolin in the hippocampus and cortex of the brain in AD Tg mice as compared to vehicle-treated mice. TSA also increased the levels of γ-secretase and β-secretase activity in the brain. However, TSA did not show any effect on the activities or the expression levels of NEP and IDE in the brain. Furthermore, TSA treatment of AD Tg mice showed no change in the amyloid load (percent of examined area occupied by amyloid plaques) in the hippocampus and cortex, suggesting that TSA treatment did not result in the reduction of amyloid load. Interestingly, TSA prevented the formation of new amyloid deposits but increased the size of existing plaques. TSA treatment did not cause any apoptosis in the brain. These results suggest that TSA increases gelsolin expression in the brain, but the pleiotropic effects of TSA negate the anti-amyloidogenic effect of gelsolin in AD Tg mice.
Keywords: Alzheimer's disease, amyloid plaques, gelsolin, histone deacetylase, insulin-degrading enzyme, neprilysin, secretases, transgenic mice, trichostatin A.
Current Alzheimer Research
Title:Effect of Trichostatin A on Gelsolin Levels, Proteolysis of Amyloid Precursor Protein, and Amyloid Beta-Protein Load in the Brain of Transgenic Mouse Model of Alzheimer's Disease
Volume: 11 Issue: 10
Author(s): Wenzhong Yang, Abha Chauhan, Jerzy Wegiel, Izabela Kuchna, Feng Gu and Ved Chauhan
Affiliation:
Keywords: Alzheimer's disease, amyloid plaques, gelsolin, histone deacetylase, insulin-degrading enzyme, neprilysin, secretases, transgenic mice, trichostatin A.
Abstract: In vivo and in vitro studies have shown that gelsolin is an anti-amyloidogenic protein. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the expression of gelsolin. Fibrillized amyoid beta-protein (Aβ) is a key constituent of amyloid plaques in the brains of patients with Alzheimer’s disease (AD). We studied the effects of TSA on the levels of gelsolin; amyloid precursor protein (APP); proteolytic enzymes (γ-secretase and β-secretase) responsible for the production of Aβ; Aβ-cleaving enzymes, i.e., neprilysin (NEP) and insulin-degrading enzyme (IDE); and amyloid load in the double transgenic (Tg) APPswe/PS1δE9 mouse model of AD. Intraperitoneal injection of TSA for two months (9–11 months of age) resulted in decreased activity of HDAC, and increased levels of gelsolin in the hippocampus and cortex of the brain in AD Tg mice as compared to vehicle-treated mice. TSA also increased the levels of γ-secretase and β-secretase activity in the brain. However, TSA did not show any effect on the activities or the expression levels of NEP and IDE in the brain. Furthermore, TSA treatment of AD Tg mice showed no change in the amyloid load (percent of examined area occupied by amyloid plaques) in the hippocampus and cortex, suggesting that TSA treatment did not result in the reduction of amyloid load. Interestingly, TSA prevented the formation of new amyloid deposits but increased the size of existing plaques. TSA treatment did not cause any apoptosis in the brain. These results suggest that TSA increases gelsolin expression in the brain, but the pleiotropic effects of TSA negate the anti-amyloidogenic effect of gelsolin in AD Tg mice.
Export Options
About this article
Cite this article as:
Yang Wenzhong, Chauhan Abha, Wegiel Jerzy, Kuchna Izabela, Gu Feng and Chauhan Ved, Effect of Trichostatin A on Gelsolin Levels, Proteolysis of Amyloid Precursor Protein, and Amyloid Beta-Protein Load in the Brain of Transgenic Mouse Model of Alzheimer's Disease, Current Alzheimer Research 2014; 11 (10) . https://dx.doi.org/10.2174/1567205011666141107125531
DOI https://dx.doi.org/10.2174/1567205011666141107125531 |
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
-
Novel Oral Anticoagulants: Recommendations for Patient Evaluation, Treatment Initiation, Follow-up and Perioperative Management
Cardiovascular & Hematological Disorders-Drug Targets Natural Killer T Cells as Targets for Therapeutic Intervention in Autoimmune Diseases
Current Pharmaceutical Design Selenium in the Therapy of Neurological Diseases. Where is it Going?
Current Neuropharmacology Efficacy and Cardiovascular Safety of GLP-1 Receptor Analogues
Current Drug Safety Updates on the Role of FDG-PET/CT in Gynecological Malignancies
Current Molecular Imaging (Discontinued) Pre-therapy Iodine-131 Uptake Value as a Prediction Method for Metastatic Lymph Node Status in Patients with Differentiated Thyroid Carcinoma
Current Medical Imaging Advances in Hydrogels Applied to Degenerative Diseases
Current Pharmaceutical Design Cancer Imaging Agents for Positron Emission Tomography: Beyond FDG
Current Medical Imaging Liver-Enriched Transcription Factors and Their Role in Regulating UDP Glucuronosyltransferase Gene Expression
Current Drug Metabolism MicroRNAs and Cardiac Conduction
Current Drug Targets Multifunctional Anti-Cancer Nano-Platforms are Moving to Clinical Trials
Current Drug Metabolism Applications of Protein Microarray Technology
Combinatorial Chemistry & High Throughput Screening Nuclear Receptors as Potential Targets for Modulating Reverse Cholesterol Transport
Current Topics in Medicinal Chemistry Molecular Targeting of Acid Ceramidase: Implications to Cancer Therapy
Current Drug Targets The PKB/AKT Pathway in Cancer
Current Pharmaceutical Design Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation
Current Pharmaceutical Design Sleep and the Immune System
Current Immunology Reviews (Discontinued) Counter-Regulatory Role of Bile Acid Activated Receptors in Immunity and Inflammation
Current Molecular Medicine FOXM1 and its Oncogenic Signaling in Gastric Cancer
Recent Patents on Anti-Cancer Drug Discovery Functions of MAPR (Membrane-Associated Progesterone Receptor) Family Members As Heme/Steroid-Binding Proteins
Current Protein & Peptide Science