Abstract
Amyloid-β peptide (Aβ) oligomers, characteristic symptom of Alzheimer’s
disease (AD), have been identified as the most neurotoxic species and
significant contributors to neurodegeneration in AD. However, due to
their transient and heterogeneous nature, the high-resolution structures
and exact pathogenic processes of Aβ oligomers are currently unknown.
Using light-controlled molecular tweezers (LMTs), we describe a method
for precisely capturing specific Aβ oligomers produced from synthetic Aβ
and AD animal models. Light irradiation can activate LMTs, which are
composed of two Aβ-targeting pentapeptides (KLVFF) motifs and a rigid
azobenzene (azo) derivative, to form a tweezer-like cis configuration
that preferentially binds to specifc oligomers matching the space of the
tweezers via multivalent interactions of KLVFF motifs with the
oligomers. Surprisingly, cis-LMTs can immobilize the captured oligomers
in transgenic Caenorhabditis elegans (C. elegans) in vivo under light
irradiation. The LMTs may serve as spatiotemporally controllable
molecular tools to extract specific native oligomers for the structure
and function studies via their reversible photoisomerization, which
would improve the understanding of the toxic mechanisms of Aβ oligomers
and development of oligomer-targeted diagnosis and therapy.