A bifunctional fluorescent probe for simultaneous imaging of myelin integrity and β-amyloid plaques in Alzheimer's disease progression

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. While β-amyloid (Aβ) plaque deposition in the grey matter is a hallmark of AD, growing evidence suggests that substantial white matter abnormalities, particularly myelin degradation and axonal damage, also contribute to disease pathogenesis. However, the mechanistic interplay between Aβ aggregation and myelin disruption remains poorly understood, largely due to the lack of molecular tools capable of concurrently mapping both pathological features with high spatial resolution. Here, we report NQPI6, a novel bifunctional, dual-emission fluorescent probe that enables simultaneous and selective imaging of myelin integrity and Aβ plaques in brain tissues. NQPI6 emits a strong green fluorescence in lipid-rich myelin sheaths (λ_ex, 488 nm; λ_em 530–565 nm), allowing high-contrast, three-dimensional visualization of white matter structures. Concurrently, the probe exhibits intense red fluorescence upon binding to aggregated Aβ species (λ_ex, 561 nm; λ_em, 690–730 nm), enabling the precise delineation of plaque distribution. Utilizing NQPI6 in transgenic AD model mice, we achieved co-localized imaging of Aβ plaques and varying degrees of demyelination across distinct brain regions and disease stages. These spatial correlations uncovered a dynamic relationship between plaque accumulation and local myelin damage during AD progression. This work presents a powerful chemical imaging platform for investigating the spatiotemporal crosstalk between Aβ deposition and myelin degeneration, offering new insights into AD pathogenesis and facilitating future diagnostic and therapeutic strategies.