Abstract
Amyloid beta (Aβ) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates. Among other considered strategies, the multi-target approach has been proposed as a more suitable potential therapy, precisely due to the multifactorial nature of AD. In this context, we recently identified ASS234, a novel compound that possesses a significant multipotent profile since it is able to inhibit cholinesterase and monoamine oxidase enzymes as well as to interfere in Aβ aggregation process. In this work, we investigated more in detail the effects of ASS234 on Aβ aggregation and toxicity in vitro as well as we explored its ability to penetrate to the CNS. We report that ASS234 inhibited Aβ1-42 self-aggregation more efficiently than that of Aβ1-40, limiting the formation of fibrillar and oligomeric species. Additionally, ASS234 completely blocked the aggregation mediated by AChE of both Aβ1-42 and Aβ1-40, showing a dual binding site to AChE. Interestingly, ASS234 significantly reduced Aβ1-42-mediated toxicity in SH-SY5Y human neuroblastoma cells through the prevention of the mitochondrial apoptosis pathway activation. Also importantly, we observed a significant ability of ASS234 to capture free-radical species in vitro as well as a potent effect in preventing the Aβ1-42-induced depletion of antioxidant enzymes (catalase and SOD-1). Finally, we report the capability of ASS234 to cross the bloodbrain barrier. Overall, our in vitro results show that ASS234 may have an impact on different processes involved in AD pathogenesis and provide evidences that it has encouraging attributes as a therapeutic lead compound.
Keywords: Alzheimer’s disease therapy, amyloid β, cholinesterase inhibitors, multi-target directed ligand, neuroprotection, propargylamine.
Current Alzheimer Research
Title:Multipotent, Permeable Drug ASS234 Inhibits Aβ Aggregation, Possesses Antioxidant Properties and Protects from Aβ-induced Apoptosis In Vitro
Volume: 10 Issue: 8
Author(s): Irene Bolea, Alejandro Gella, Leticia Monjas, Concepción Pérez, María Isabel Rodríguez-Franco, José Marco-Contelles, Abdelouahid Samadi and Mercedes Unzeta
Affiliation:
Keywords: Alzheimer’s disease therapy, amyloid β, cholinesterase inhibitors, multi-target directed ligand, neuroprotection, propargylamine.
Abstract: Amyloid beta (Aβ) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates. Among other considered strategies, the multi-target approach has been proposed as a more suitable potential therapy, precisely due to the multifactorial nature of AD. In this context, we recently identified ASS234, a novel compound that possesses a significant multipotent profile since it is able to inhibit cholinesterase and monoamine oxidase enzymes as well as to interfere in Aβ aggregation process. In this work, we investigated more in detail the effects of ASS234 on Aβ aggregation and toxicity in vitro as well as we explored its ability to penetrate to the CNS. We report that ASS234 inhibited Aβ1-42 self-aggregation more efficiently than that of Aβ1-40, limiting the formation of fibrillar and oligomeric species. Additionally, ASS234 completely blocked the aggregation mediated by AChE of both Aβ1-42 and Aβ1-40, showing a dual binding site to AChE. Interestingly, ASS234 significantly reduced Aβ1-42-mediated toxicity in SH-SY5Y human neuroblastoma cells through the prevention of the mitochondrial apoptosis pathway activation. Also importantly, we observed a significant ability of ASS234 to capture free-radical species in vitro as well as a potent effect in preventing the Aβ1-42-induced depletion of antioxidant enzymes (catalase and SOD-1). Finally, we report the capability of ASS234 to cross the bloodbrain barrier. Overall, our in vitro results show that ASS234 may have an impact on different processes involved in AD pathogenesis and provide evidences that it has encouraging attributes as a therapeutic lead compound.
Export Options
About this article
Cite this article as:
Bolea Irene, Gella Alejandro, Monjas Leticia, Pérez Concepción, Rodríguez-Franco Isabel María, Marco-Contelles José, Samadi Abdelouahid and Unzeta Mercedes, Multipotent, Permeable Drug ASS234 Inhibits Aβ Aggregation, Possesses Antioxidant Properties and Protects from Aβ-induced Apoptosis In Vitro, Current Alzheimer Research 2013; 10 (8) . https://dx.doi.org/10.2174/15672050113109990151
DOI https://dx.doi.org/10.2174/15672050113109990151 |
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
-
Poly(ADP-Ribosylation): Beneficial Effects of Its Inhibition
Current Enzyme Inhibition Nampt/Visfatin/PBEF: A Functionally Multi-faceted Protein with a Pivotal Role in Malignant Tumors
Current Pharmaceutical Design Ceramide: Therapeutic Potential in Combination Therapy for Cancer Treatment
Current Drug Metabolism Cancer Vaccines: Emphasis on Pediatric Cancers
Current Pharmaceutical Design Aflibercept (VEGF-TRAP): The Next Anti-VEGF Drug
Inflammation & Allergy - Drug Targets (Discontinued) Exploring the Role of Nerve Growth Factor in Multiple Sclerosis: Implications in Myelin Repair
CNS & Neurological Disorders - Drug Targets Evaluation of Non-Coding RNAs as Potential Targets in Head and Neck Squamous Cell Carcinoma Cancer Stem Cells
Current Drug Targets Interaction of Proteins with Lipid Rafts Through Glycolipid-Binding Domains:Biochemical Background and Potential Therapeutic Applications
Current Medicinal Chemistry Nano-Enabled Drug Delivery in Cancer Therapy: Literature Analysis Using the MeSH System
Pharmaceutical Nanotechnology Role of Generation, Architecture, pH and Ionic Strength on Successful siRNA Delivery and Transfection by Hybrid PPV-PAMAM Dendrimers
Current Medicinal Chemistry Conformational Diseases and Structure-Toxicity Relationships: Lessons from Prion-Derived Peptides
Current Protein & Peptide Science Neuropeptide FF Inhibits LPS-Mediated Osteoclast Differentiation of RAW264.7 Cells
Protein & Peptide Letters Role of Resveratrol in Modulating microRNAs in Human Diseases: From Cancer to Inflammatory Disorder
Current Medicinal Chemistry B7-H3-targeted Radioimmunotherapy of Human Cancer
Current Medicinal Chemistry Small Heat Shock Proteins (sHSPs) As Potential Drug Targets
Current Pharmaceutical Biotechnology New Insights on the Antitumoral Properties of Prodiginines
Current Medicinal Chemistry The Possible Involvement of Glycogen Synthase Kinase-3 (GSK-3) in Diabetes, Cancer and Central Nervous System Diseases
Current Pharmaceutical Design Cytotoxic Effect of the Red Beetroot (Beta vulgaris L.) Extract Compared to Doxorubicin (Adriamycin) in the Human Prostate (PC-3) and Breast (MCF-7) Cancer Cell Lines
Anti-Cancer Agents in Medicinal Chemistry Vaccine Ingredients: Components that Influence Vaccine Efficacy
Mini-Reviews in Medicinal Chemistry MicroRNAs Involved in Oxidative Stress Processes Regulating Physiological and Pathological Responses
MicroRNA