Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid ß Aggregates in Alzheimer's Disease.
J Am Chem Soc
; 143(27): 10462-10476, 2021 07 14.
Article
em En
| MEDLINE
| ID: mdl-34213901
ABSTRACT
Alzheimer's Disease (AD) is the most common neurodegenerative disease, and efficient therapeutic and early diagnostic agents for AD are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated by linking a hydrophobic amyloid-binding distyrylbenzene fragment with a hydrophilic triazamacrocycle, which dramatically increases the binding affinity toward various amyloid ß (Aß) peptide aggregates, especially for soluble Aß oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of LS-4-treated brain sections reveals that LS-4 can penetrate the blood-brain barrier and bind to the Aß oligomers in vivo. In addition, the treatment of 5xFAD mice with LS-4 reduces the amount of both amyloid plaques and associated phosphorylated tau aggregates vs the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure of LS-4 can enhance the electrostatic interactions with the polar residues of the Aß species. Finally, exploiting the Cu2+-chelating property of the triazamacrocycle, we performed a series of imaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate to a significantly larger extent in the 5xFAD mouse brains vs the wild-type controls. Overall, these results illustrate that the novel strategy, to employ an amphiphilic molecule containing a hydrophilic moiety attached to a hydrophobic amyloid-binding fragment, can increase the binding affinity for both soluble and insoluble Aß aggregates and can thus be used to detect and regulate various Aß species in AD.
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Base de dados:
MEDLINE
Assunto principal:
Estirenos
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Desenho de Fármacos
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Peptídeos beta-Amiloides
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Fármacos Neuroprotetores
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Doença de Alzheimer
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article