Abstract
Inhibition of the β-secretase, BACE1, which cleaves amyloid precursor protein (APP) to produce β-amyloid protein (Aβ), is thought to be a feasible therapeutic strategy for Alzheimer’s disease. Reticulon (RTN) proteins such as RTN3 have been identified as membrane proteins that interact with BACE1 and inhibit its Aβ-generating activity. In this study, we investigated whether RTN3 can regulate Aβ production in vivo, using transgenic (Tg) mice expressing APP with Swedish and London mutations (APP Tg mice) and those expressing RTN3; the latter mice showed ~1.4-fold higher expression levels of RTN3 protein in the cerebral cortex than non-Tg controls. We analyzed the brains of single APP Tg and double APP/RTN3 Tg mice at the age of approximately 15 months. The levels of secreted APP-β, a direct BACE1 cleavage product of APP, in Tris-soluble fraction were considerably reduced in the hippocampus and cerebral cortex of APP/RTN3 Tg mice relative to those in APP Tg mice. Immunohistochemical analyses demonstrated that Aβ burden and plaques were significantly (by approximately 50%) decreased in both the hippocampus and cerebral cortex of double Tg mice compared to APP Tg mice. Furthermore, the levels of guanidine-soluble Aβ40 and Aβ42 in these brain regions of APP/RTN3 Tg mice were relatively lower than those in APP Tg mice. These findings indicate that even a small increase in RTN3 expression exerts suppressive effects on amyloidogenic processing of APP and Aβ accumulation through modulation of BACE1 activity in vivo, and suggest that induction of RTN3 might be an effective therapeutic strategy against Alzheimer’s disease.
Keywords: Alzheimer’s disease, β-amyloid, β-secretase, BACE1, reticulon; transgenic mice
Current Alzheimer Research
Title:Reduction of β-Amyloid Accumulation by Reticulon 3 in Transgenic Mice
Volume: 10 Issue: 2
Author(s): Wataru Araki, Akiko Oda, Kazumi Motoki, Kotaro Hattori, Masayuki Itoh, Shigeki Yuasa, Yoshihiro Konishi, Ryong-Woon Shin, Akira Tamaoka and Koichi Ogino
Affiliation:
Keywords: Alzheimer’s disease, β-amyloid, β-secretase, BACE1, reticulon; transgenic mice
Abstract: Inhibition of the β-secretase, BACE1, which cleaves amyloid precursor protein (APP) to produce β-amyloid protein (Aβ), is thought to be a feasible therapeutic strategy for Alzheimer’s disease. Reticulon (RTN) proteins such as RTN3 have been identified as membrane proteins that interact with BACE1 and inhibit its Aβ-generating activity. In this study, we investigated whether RTN3 can regulate Aβ production in vivo, using transgenic (Tg) mice expressing APP with Swedish and London mutations (APP Tg mice) and those expressing RTN3; the latter mice showed ~1.4-fold higher expression levels of RTN3 protein in the cerebral cortex than non-Tg controls. We analyzed the brains of single APP Tg and double APP/RTN3 Tg mice at the age of approximately 15 months. The levels of secreted APP-β, a direct BACE1 cleavage product of APP, in Tris-soluble fraction were considerably reduced in the hippocampus and cerebral cortex of APP/RTN3 Tg mice relative to those in APP Tg mice. Immunohistochemical analyses demonstrated that Aβ burden and plaques were significantly (by approximately 50%) decreased in both the hippocampus and cerebral cortex of double Tg mice compared to APP Tg mice. Furthermore, the levels of guanidine-soluble Aβ40 and Aβ42 in these brain regions of APP/RTN3 Tg mice were relatively lower than those in APP Tg mice. These findings indicate that even a small increase in RTN3 expression exerts suppressive effects on amyloidogenic processing of APP and Aβ accumulation through modulation of BACE1 activity in vivo, and suggest that induction of RTN3 might be an effective therapeutic strategy against Alzheimer’s disease.
Export Options
About this article
Cite this article as:
Araki Wataru, Oda Akiko, Motoki Kazumi, Hattori Kotaro, Itoh Masayuki, Yuasa Shigeki, Konishi Yoshihiro, Shin Ryong-Woon, Tamaoka Akira and Ogino Koichi, Reduction of β-Amyloid Accumulation by Reticulon 3 in Transgenic Mice, Current Alzheimer Research 2013; 10 (2) . https://dx.doi.org/10.2174/1567205011310020003
DOI https://dx.doi.org/10.2174/1567205011310020003 |
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
-
Astrocytic Target Mechanisms in Epilepsy
Current Medicinal Chemistry Complementary and Alternative Medicine for the Treatment of Insomnia: An Overview of Scientific Evidence from 2008 to 2018
Current Vascular Pharmacology Diabetes and Periodontal Diseases: Interplay and Links
Current Diabetes Reviews Oxidative/Nitrosative Brain Damage in Stress: Possible Target for Neuropsychopharmacological Drugs
Current Medicinal Chemistry - Central Nervous System Agents Dendrimers as an Effective Nanocarrier in Cardiovascular Disease
Current Pharmaceutical Design Cardiovascular Pharmacogenetics of Anti-Thrombotic Agents and Non-Steroidal Anti-Inflammatory Drugs
Current Molecular Medicine Mitigating Alzheimer’s Disease with Natural Polyphenols: A Review
Current Alzheimer Research Mucopolysaccharidosis Type II (Hunter Syndrome): Clinical Picture and Treatment
Current Pharmaceutical Biotechnology Strategies Targeting Soluble β-Amyloid Oligomers and their Application to Early Diagnosis of Alzheimer’s Disease
Current Alzheimer Research Intestinal Barrier Dysfunction Participates in the Pathophysiology of Ischemic Stroke
CNS & Neurological Disorders - Drug Targets A Feature-Free 30-Disease Pathological Brain Detection System by Linear Regression Classifier
CNS & Neurological Disorders - Drug Targets In Silico Search and Toxicology Prediction of Novel Potential β-Secretase Inhibitors in Alzheimers Disease
Current Bioactive Compounds Are Raw Scores on Memory Tests Better than Age- and Education- Adjusted Scores for Predicting Progression from Amnesic Mild Cognitive Impairment to Alzheimer Disease ?
Current Alzheimer Research Levels of Estrogen Receptors α and β in Frontal Cortex of Patients with Alzheimers Disease: Relationship to Mini-Mental State Examination Scores
Current Alzheimer Research Bone Marrow-Derived Mesenchymal Stem Cells Contribute to the Reduction of Amyloid-β Deposits and the Improvement of Synaptic Transmission in a Mouse Model of Pre-Dementia Alzheimer’s Disease
Current Alzheimer Research Neuroinflammation: Microglial Activation During Sepsis
Current Neurovascular Research From Antioxidant Chelators to Site-Activated Multi-Target Chelators Targeting Hypoxia Inducing Factor, Beta-Amyloid, Acetylcholinesterase and Monoamine Oxidase A/B
Mini-Reviews in Medicinal Chemistry Increasing Testosterone Levels and Effects on Cognitive Functions in Elderly Men and Women: A Review
Current Drug Targets - CNS & Neurological Disorders The Role of Minocycline in Ischemia-Reperfusion Injury: A Comprehensive Review of an Old Drug with New Implications
Recent Patents on Cardiovascular Drug Discovery Exploration of Potent Multi-target-directed-ligands as Anti-alzheimer’s Disease Agents: A Moiety Based Review
Mini-Reviews in Medicinal Chemistry