Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease
Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Existent therapies are directed at alleviating some symptoms, but are not effective in altering the course of the disease. Methods: Based on our previous study that showed that an Aβ-inter...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-07-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996120302138 |
| _version_ | 1818742086830129152 |
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| author | Christian Peters Denisse Bascuñán Carlos F. Burgos Catalina Bobadilla Juliana González-Sanmiguel Subramanian Boopathi Nicolás Riffo Eduardo J. Fernández-Pérez María Elena Tarnok Luis Felipe Aguilar Wendy Gonzalez Luis G. Aguayo |
| author_facet | Christian Peters Denisse Bascuñán Carlos F. Burgos Catalina Bobadilla Juliana González-Sanmiguel Subramanian Boopathi Nicolás Riffo Eduardo J. Fernández-Pérez María Elena Tarnok Luis Felipe Aguilar Wendy Gonzalez Luis G. Aguayo |
| author_sort | Christian Peters |
| collection | DOAJ |
| description | Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Existent therapies are directed at alleviating some symptoms, but are not effective in altering the course of the disease. Methods: Based on our previous study that showed that an Aβ-interacting small peptide protected against the toxic effects of amyloid-beta peptide (Aβ), we carried out an array of in silico, in vitro, and in vivo assays to identify a molecule having neuroprotective properties. Results: In silico studies showed that the molecule, referred to as M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine), was able to interact with the Aβ peptide. Additionally, in vitro assays showed that M30 blocked Aβ aggregation, association to the plasma membrane, synaptotoxicity, intracellular calcium, and cellular toxicity, while in vivo experiments demonstrated that M30 induced a neuroprotective effect by decreasing the toxicity of Aβ in the dentate gyrus of the hippocampus and improving the alteration in spatial memory in behavior assays. Discussion: Therefore, we propose that this new small molecule could be a useful candidate for the additional development of a treatment against AD since it appears to block multiple steps in the amyloid cascade. Overall, since there are no drugs that effectively block the progression of AD, this approach represents an innovative strategy. Significance: Currently, there is no effective treatment for AD and the expectations to develop an effective therapy are low. Using in silico, in vitro, and in vivo experiments, we identified a new compound that is able to inhibit Aβ-induced neurotoxicity, specifically aggregation, association to neurons, synaptic toxicity, calcium dyshomeostasis and memory impairment induced by Aβ. Because Aβ toxicity is central to AD progression, the inhibition mediated by this new molecule might be useful as a therapeutic tool. |
| first_indexed | 2024-12-18T02:06:56Z |
| format | Article |
| id | doaj.art-7e1dc5c882e3420aafe21c4f7b92bb89 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-18T02:06:56Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-7e1dc5c882e3420aafe21c4f7b92bb892022-12-21T21:24:34ZengElsevierNeurobiology of Disease1095-953X2020-07-01141104938Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's diseaseChristian Peters0Denisse Bascuñán1Carlos F. Burgos2Catalina Bobadilla3Juliana González-Sanmiguel4Subramanian Boopathi5Nicolás Riffo6Eduardo J. Fernández-Pérez7María Elena Tarnok8Luis Felipe Aguilar9Wendy Gonzalez10Luis G. Aguayo11Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, ChileLaboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, ChileLaboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, ChileLaboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, ChileLaboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, ChileThe Center for Bioinformatics and Molecular Simulations (CBSM), Universidad de Talca, Talca, ChileLaboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, ChileLaboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, ChileLaboratory of Photophysics and Molecular Spectroscopy, Chemistry, Pontificia Universidad Católica de Valparaíso, Valparaíso, ChileLaboratory of Photophysics and Molecular Spectroscopy, Chemistry, Pontificia Universidad Católica de Valparaíso, Valparaíso, ChileThe Center for Bioinformatics and Molecular Simulations (CBSM), Universidad de Talca, Talca, Chile; Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, Talca, ChileLaboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, Chile; Corresponding author.Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Existent therapies are directed at alleviating some symptoms, but are not effective in altering the course of the disease. Methods: Based on our previous study that showed that an Aβ-interacting small peptide protected against the toxic effects of amyloid-beta peptide (Aβ), we carried out an array of in silico, in vitro, and in vivo assays to identify a molecule having neuroprotective properties. Results: In silico studies showed that the molecule, referred to as M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine), was able to interact with the Aβ peptide. Additionally, in vitro assays showed that M30 blocked Aβ aggregation, association to the plasma membrane, synaptotoxicity, intracellular calcium, and cellular toxicity, while in vivo experiments demonstrated that M30 induced a neuroprotective effect by decreasing the toxicity of Aβ in the dentate gyrus of the hippocampus and improving the alteration in spatial memory in behavior assays. Discussion: Therefore, we propose that this new small molecule could be a useful candidate for the additional development of a treatment against AD since it appears to block multiple steps in the amyloid cascade. Overall, since there are no drugs that effectively block the progression of AD, this approach represents an innovative strategy. Significance: Currently, there is no effective treatment for AD and the expectations to develop an effective therapy are low. Using in silico, in vitro, and in vivo experiments, we identified a new compound that is able to inhibit Aβ-induced neurotoxicity, specifically aggregation, association to neurons, synaptic toxicity, calcium dyshomeostasis and memory impairment induced by Aβ. Because Aβ toxicity is central to AD progression, the inhibition mediated by this new molecule might be useful as a therapeutic tool.http://www.sciencedirect.com/science/article/pii/S0969996120302138AlzheimerSmall moleculeNovelMulti-stepDrugTherapy |
| spellingShingle | Christian Peters Denisse Bascuñán Carlos F. Burgos Catalina Bobadilla Juliana González-Sanmiguel Subramanian Boopathi Nicolás Riffo Eduardo J. Fernández-Pérez María Elena Tarnok Luis Felipe Aguilar Wendy Gonzalez Luis G. Aguayo Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease Neurobiology of Disease Alzheimer Small molecule Novel Multi-step Drug Therapy |
| title | Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease |
| title_full | Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease |
| title_fullStr | Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease |
| title_full_unstemmed | Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease |
| title_short | Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer's disease |
| title_sort | characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in alzheimer s disease |
| topic | Alzheimer Small molecule Novel Multi-step Drug Therapy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996120302138 |
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