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 β (Aβ) peptide aggregates, especially for soluble Aβ 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 Aβ 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 Aβ 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 Aβ aggregates and can thus be used to detect and regulate various Aβ species in AD.
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Authors | Liang Sun, Hong-Jun Cho, Soumyo Sen, Andres S Arango, Truc T Huynh, Yiran Huang, Nilantha Bandara, Buck E Rogers, Emad Tajkhorshid, Liviu M Mirica |
Journal | Journal of the American Chemical Society
(J Am Chem Soc)
Vol. 143
Issue 27
Pg. 10462-10476
(07 14 2021)
ISSN: 1520-5126 [Electronic] United States |
PMID | 34213901
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Amyloid
- Amyloid beta-Peptides
- Neuroprotective Agents
- Peptide Fragments
- Styrenes
- distyrylbenzene
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Topics |
- Alzheimer Disease
(drug therapy)
- Amyloid
- Amyloid beta-Peptides
(chemistry)
- Animals
- Drug Design
- Mice
- Mice, Transgenic
- Molecular Structure
- Neuroprotective Agents
(chemical synthesis, pharmacology)
- Peptide Fragments
- Plaque, Amyloid
- Positron-Emission Tomography
- Protein Binding
- Styrenes
(chemistry)
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