Abstract
Amyloid beta (Aβ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ)-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer’s disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished Aβ-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function.
Keywords: ABAD inhibitors, adenosine-5'-triphosphate, amyloid beta, benzothiazole amino phosphonates, cytochrome c oxidase, mitochondrial dysfunction.
Current Alzheimer Research
Title:Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction
Volume: 11 Issue: 2
Author(s): Koteswara R. Valaasani, Qinru Sun, Gang Hu, Jianping Li, Fang Du, Yaopeng Guo, Emily A. Carlson, Xueqi Gan and Shirley S. Yan
Affiliation:
Keywords: ABAD inhibitors, adenosine-5'-triphosphate, amyloid beta, benzothiazole amino phosphonates, cytochrome c oxidase, mitochondrial dysfunction.
Abstract: Amyloid beta (Aβ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ)-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer’s disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished Aβ-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function.
Export Options
About this article
Cite this article as:
Valaasani R. Koteswara, Sun Qinru, Hu Gang, Li Jianping, Du Fang, Guo Yaopeng, Carlson A. Emily, Gan Xueqi and Yan S. Shirley, Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction, Current Alzheimer Research 2014; 11 (2) . https://dx.doi.org/10.2174/1567205011666140130150108
DOI https://dx.doi.org/10.2174/1567205011666140130150108 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
- 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
-
Shear Stress-sensitive Carriers for Localized Drug Delivery
Current Pharmaceutical Design Default Mode Network Connectivity and Related White Matter Disruption in Type 2 Diabetes Mellitus Patients Concurrent with Amnestic Mild Cognitive Impairment
Current Alzheimer Research Past, Present and Future Therapeutics for Cerebellar Ataxias
Current Neuropharmacology Can Tea Consumption be a Safe and Effective Therapy Against Diabetes Mellitus-Induced Neurodegeneration?
Current Neuropharmacology Glutamate and Schizophrenia
Current Neuropharmacology Management of Hypertension-Journey from Single Drug Therapy to Multitargeted Ligand Therapy: A Clinical Overview
Current Clinical Pharmacology Vascular Oxidative Stress and Mitochondrial Failure in the Pathobiology of Alzheimer’s Disease: A New Approach to Therapy
CNS & Neurological Disorders - Drug Targets Targeting Neurotrophin Receptors in the Central Nervous System
CNS & Neurological Disorders - Drug Targets New Approaches for the Treatment of Mental Disorders Comorbid with Inflammatory Diseases
Current Topics in Medicinal Chemistry Minocycline Mediated Mitochondrial Cytoprotection: Premises for Therapy of Cerebrovascular and Neurodegenerative Diseases
Current Drug Targets Nicotinic Receptors and the Treatment of Attentional and Cognitive Deficits in Neuropsychiatric Disorders: Focus on the α7 Nicotinic Acetylcholine Receptor as a Promising Drug Target for Schizophrenia
Central Nervous System Agents in Medicinal Chemistry Cerebrospinal-fluid Alzheimer’s Disease Biomarkers and Blood-Brain Barrier Integrity in a Natural Population of Cognitive Intact Parkinson’s Disease Patients
CNS & Neurological Disorders - Drug Targets Enhanced Proinflammatory State and Autoimmune Activation: a Breakthrough to Understanding Chronic Diseases
Current Pharmaceutical Design In Vitro Models of the Blood-Brain Barrier: When to Use Which?
Current Medicinal Chemistry - Central Nervous System Agents Cannabinoids
Current Drug Targets - CNS & Neurological Disorders Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: A Review
Current Drug Therapy The Developing Utility of Zebrafish Models for Cognitive Enhancers Research
Current Neuropharmacology The Peripheral Nervous System and the Pathogenesis of Prion Diseases
Current Molecular Medicine Obstructive Sleep Apnoea Syndrome and Diabetes. Fortuitous Association or Interaction?
Current Diabetes Reviews Structural MRI Predictors of Late-Life Cognition Differ Across African Americans, Hispanics, and Whites
Current Alzheimer Research