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
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
-
Avian Cytokines - An Overview
Current Pharmaceutical Design A Fatal Case of Acute Interstitial Pneumonia (AIP) in a Woman Affected by Glioblastoma
Current Drug Safety Overexpression and Purification of Recombinant Eel Calcitonin and Its Phylogenetic Analysis
Protein & Peptide Letters The p53-Mdm2 Pathway: Targets for the Development of New Anticancer Therapeutics
Mini-Reviews in Medicinal Chemistry A Progressive Review of V600E-B-RAF-Dependent Melanoma and Drugs Inhibiting It
Mini-Reviews in Medicinal Chemistry Metabolic Syndrome and Cardiometabolic Risk Factors
Current Vascular Pharmacology Homology-Free Prediction of Functional Class of Proteins and Peptides by Support Vector Machines
Current Protein & Peptide Science Hepatic Cell Lines for Drug Hepatotoxicity Testing: Limitations and Strategies to Upgrade their Metabolic Competence by Gene Engineering
Current Drug Metabolism Obesity Modulation - The Role in Carcinogenesis
Anti-Cancer Agents in Medicinal Chemistry Review of Selected Patents for Cancer Therapy Targeting Tumor Angiogenesis
Recent Patents on Anti-Cancer Drug Discovery Management of Gestational Trophoblastic Diseases-An Update
Reviews on Recent Clinical Trials Phosphodiesterase Inhibitors as a Target for Cognition Enhancement in Aging and Alzheimer’s Disease: A Translational Overview
Current Pharmaceutical Design Medullary Thyroid Cancer: New Targeted Molecular Therapies
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Modulation of Sensitivity to Antitumor Agents by Targeting the MAPK Survival Pathway
Current Pharmaceutical Design Multiscale Modelling of Relationships between Protein Classes and Drug Behavior Across all Diseases Using the CANDO Platform
Mini-Reviews in Medicinal Chemistry Discovery and Development of Endocannabinoid-Hydrolyzing Enzyme Inhibitors
Current Topics in Medicinal Chemistry RNA Splicing: Basic Aspects Underlie Antitumor Targeting
Recent Patents on Anti-Cancer Drug Discovery Patent Selections
Recent Patents on Inflammation & Allergy Drug Discovery The Modulating Effects of Endogenous Substances on Drug Metabolising Enzymes and Implications for Inter-Individual Variability and Quantitative Prediction
Current Drug Metabolism Heat Shock Proteins: Therapeutic Perspectives in Inflammatory Disorders
Recent Patents on Inflammation & Allergy Drug Discovery