Biophysical and in Vivo Studies Identify a New Natural-Based Polyphenol, Counteracting Aβ Oligomerization in Vitro and Aβ Oligomer-Mediated Memory Impairment and Neuroinflammation in an Acute Mouse Model of Alzheimer’s Disease
| Autor: | Gianluigi Forloni, Pietro La Vitola, Luca Banfi, Giulia Santamaria, Claudia Fracasso, Denise Galante, Claudia Balducci, Jacopo Lucchetti, Chiara Lambruschini, Laura Ragona, Simona Tomaselli, Cristina D'Arrigo, Edoardo Brandi, Katiuscia Pagano, Lisa Moni, Henriette Molinari |
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| Rok vydání: | 2019 |
| Předmět: |
Physiology
Peptidomimetic Cognitive Neuroscience Biochemistry Oligomer Protein Structure Secondary memory Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Alzheimer Disease In vivo medicine Animals Cells Cultured Neuroinflammation 030304 developmental biology Inflammation Memory Disorders 0303 health sciences Amyloid beta-Peptides animal model Neurotoxicity Polyphenols animal model docking inflammation memory NMR polyphenols β-Amyloid Cell Biology General Medicine medicine.disease NMR Peptide Fragments In vitro Mice Inbred C57BL Molecular Docking Simulation Disease Models Animal chemistry Docking (molecular) docking Acute Disease β-Amyloid Cell activation 030217 neurology & neurosurgery |
| Zdroj: | ACS Chemical Neuroscience. 10:4462-4475 |
| ISSN: | 1948-7193 |
| Popis: | In this study natural-based complex polyphenols, obtained through a smart synthetic approach, have been evaluated for their ability to inhibit the formation of Aβ42 oligomers, the most toxic species causing synaptic dysfunction, neuroinflammation, and neuronal death leading to the onset and progression of Alzheimer's disease. In vitro neurotoxicity tests on primary hippocampal neurons have been employed to select nontoxic candidates. Solution NMR and molecular docking studies have been performed to clarify the interaction mechanism of Aβ42 with the synthesized polyphenol derivatives, and highlight the sterical and chemical requirements important for their antiaggregating activity. NMR results indicated that the selected polyphenolic compounds target Aβ42 oligomeric species. Combined NMR and docking studies indicated that the Aβ42 central hydrophobic core, namely, the 17-31 region, is the main interaction site. The length of the peptidomimetic scaffold and the presence of a guaiacol moiety were identified as important requirements for the antiaggregating activity. In vivo experiments on an Aβ42 oligomer-induced acute mouse model highlighted that the most promising polyphenolic derivative (PP04) inhibits detrimental effects of Aβ42 oligomers on memory and glial cell activation. NMR kinetic studies showed that PP04 is endowed with the chemical features of true inhibitors, strongly affecting both the Aβ42 nucleation and growth rates, thus representing a promising candidate to be further developed into an effective drug against neurodegenerative diseases of the amyloid type. |
| Databáze: | OpenAIRE |
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