Cyclopeptide-Based Fluorescent Conjugates for Monitoring Prefibrillar Aβ Nanostructures

Amyloid-β (Aβ1–42)
prefibrillar aggregates
are
considered the most neurotoxic amyloid species, yet their transient
and heterogeneous nature makes selective detection challenging. Many
fluorescent probes also fail to discriminate Aβ from homologous
peptides such as IAPP, leading to poor specificity. We report a peptide-guided
late-stage diversification strategy to generate BODIPY-based probes
highly selective for prefibrillar Aβ1–42. A rationally
engineered cyclic peptide derived from the C-terminal region of Aβ1–42
provides conformational rigidity and precise molecular recognition.
Conjugation to BODIPY fluorophores afforded peptide–dye hybrids
systematically evaluated for selectivity and photophysical response.
A controlled aggregation protocol enabling reproducible generation
of prefibrillar Aβ species was established to validate probe
performance. A Sonogashira-derived conjugate (probe 8) showed strong fluorescence turn-on and selective affinity for prefibrillar
Aβ1–42, with no response to IAPP aggregates. In neuronal
cells, probe 8 outperformed conventional antibodies,
supporting its potential for mechanistic studies and early Alzheimer’s
disease diagnostics.