Selective detection of membrane-bound amyloid-β oligomers using SERS “hot-spots”: toward early diagnostics for Alzheimer's disease

A key characteristic of Alzheimer's disease (AD) is the build-up of amyloid-β (Aβ) fibrillar aggregates, commonly known as plaques, within the brain. Current diagnostic tools, such as MRI, CT, and PET, primarily detect neurodegeneration or plaque burden, limiting their utility to advanced stages of the disorder. Thus, there is a strong need for sensitive approaches that can enable detection at the earliest. Aβ aggregation begins with the formation of small, lipophilic oligomers characterized by antiparallel β-sheet structures. Emerging evidence suggests that these oligomers associated with exosomes can traverse the blood-brain barrier, with their peripheral blood levels reflecting disease progression. However, their low abundance poses a significant detection challenge. Sensitive and selective detection of these lipophilic oligomers could provide a powerful diagnostic tool for early AD detection. In this work, we introduce a highly sensitive Surface-Enhanced Raman Spectroscopy (SERS)-based platform for detecting membrane-bound Aβ oligomers. Monodisperse silver nanoparticles (AgNPs) were functionalized with Rose Bengal (RB), a dye specific to amyloid oligomers. Separately, lipid-bilayer-coated AgNPs were used to capture lipophilic Aβ oligomers. The interaction between the oligomers and RB localized the dye molecules within SERS "hot spots" formed between the nanoparticles, leading to a robust, Aβ-concentration-dependent enhancement of the RB Raman signal. This dual-nanoconstruct system provides a promising route toward blood-based early-stage AD diagnostics.