Dataset Information

Human Albumin Impairs Amyloid ?-peptide Fibrillation Through its C-terminus: From docking Modeling to Protection Against Neurotoxicity in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extracellular deposits of amyloid ?-peptide (A?), which induces neuronal death. Monomeric A? is not toxic but tends to aggregate into ?-sheets that are neurotoxic. Therefore to prevent or delay AD onset and progression one of the main therapeutic approaches would be to impair A? assembly into oligomers and fibrils and to promote disaggregation of the preformed aggregate. Albumin is the most abundant protein in the cerebrospinal fluid and it was reported to bind A? impeding its aggregation. In a previous work we identified a 35-residue sequence of clusterin, a well-known protein that binds A?, that is highly similar to the C-terminus (CTerm) of albumin. In this work, the docking experiments show that the average binding free energy of the CTerm-A?1-42 simulations was significantly lower than that of the clusterin-A?1-42 binding, highlighting the possibility that the CTerm retains albumin's binding properties. To validate this observation, we performed in vitro structural analysis of soluble and aggregated 1??M A?1-42 incubated with 5??M CTerm, equimolar to the albumin concentration in the CSF. Reversed-phase chromatography and electron microscopy analysis demonstrated a reduction of A?1-42 aggregates when the CTerm was present. Furthermore, we treated a human neuroblastoma cell line with soluble and aggregated A?1-42 incubated with CTerm obtaining a significant protection against A?-induced neurotoxicity. These in silico and in vitro data suggest that the albumin CTerm is able to impair A? aggregation and to promote disassemble of A? aggregates protecting neurons.

SUBMITTER: Picon-Pages P

PROVIDER: S-EPMC6639691 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Human Albumin Impairs Amyloid β-peptide Fibrillation Through its C-terminus: From docking Modeling to Protection Against Neurotoxicity in Alzheimer's disease.

Picón-Pagès Pol P Bonet Jaume J García-García Javier J Garcia-Buendia Joan J Gutierrez Daniela D Valle Javier J Gómez-Casuso Carmen E S CES Sidelkivska Valeriya V Alvarez Alejandra A Perálvarez-Marín Alex A Suades Albert A Fernàndez-Busquets Xavier X Andreu David D Vicente Rubén R Oliva Baldomero B Muñoz Francisco J FJ

Computational and structural biotechnology journal 20190626

Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extracellular deposits of amyloid β-peptide (Aβ), which induces neuronal death. Monomeric Aβ is not toxic but tends to aggregate into β-sheets that are neurotoxic. Therefore to prevent or delay AD onset and progression one of the main therapeutic approaches would be to impair Aβ assembly into oligomers and fibrils and to promote disaggregation of the preformed aggregate. Albumin is the most abundant prot ...[more]

PMID: 31360335

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Project description:The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2-7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14-18), and quinolinodonepezils (19-21) are described. Pyridonepezils 15-18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19-21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC(50) (hAChE) = 0.25 ± 0.02 ?M]. Pyridonepezils 15-18 and quinolinodonepezils 20-21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC(50) (EeAChE) = 0.0167 ± 0.0002 ?M], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by A?(1-42). All compounds were effective in preventing the enhancement of AChE activity induced by A?(1-42). Compounds 2-7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by A?(1-42). Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca(2+) influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent molecules for the potential treatment of Alzheimer's disease.

Dataset Information

Human Albumin Impairs Amyloid ?-peptide Fibrillation Through its C-terminus: From docking Modeling to Protection Against Neurotoxicity in Alzheimer's disease.

Publications

Human Albumin Impairs Amyloid β-peptide Fibrillation Through its C-terminus: From docking Modeling to Protection Against Neurotoxicity in Alzheimer's disease.

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