Alzheimer’s
Diseases (AD) is the most common neurodegenerative disease, but efficient
therapeutic and early diagnosis agents for this neurological disorder are still
lacking. <a>Herein, we report the development of a novel
amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding
fragment with a hydrophilic azamacrocycle that can dramatically increase the
binding affinity towards various amyloid β (Aβ) peptide aggregates. The
developed compound exhibits uncommon fluorescence turn-on and high binding
affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon
the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated
brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier
(BBB) and bind to the Aβ oligomers <i>in vivo</i>, as confirmed by
immunostaining with an Aβ oligomer-specific antibody. In addition, the
treatment of 5xFAD mice with LS-4 significantly reduces the amount of both
amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the
vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore,
molecular dynamics simulations corroborate the observation that introducing a hydrophilic
moiety into the molecular structure can significantly enhance the electrostatic
interactions with the polar residues of the Aβ peptide species. Finally, taking
advantage of the strong Cu-chelating property of the azamacrocycle, we
performed a series of radioimaging and biodistribution studies that show the <sup>64</sup>Cu-LS-4
complex binds to the amyloid plaques and can accumulate a significantly larger
extent in the 5xFAD mice brains vs. the WT controls. Overall, these <i>in vitro</i>
and <i>in vivo</i> studies illustrate that the novel strategy to employ an amphiphilic
molecule containing a hydrophilic fragment attached to a hydrophobic amyloid
fibril-binding fragment </a><a>can increase the binding affinity of these compounds for the
soluble Aβ oligomers and can thus be used </a>to detect and regulate the soluble Aβ species in AD.
N-terminal engineering of amyloid-β-binding Affibody molecules yields improved chemical synthesis and higher binding affinity