Identification of Multicolor Fluorescent Probes for Heterogeneous A beta Deposits in Alzheimer's Disease

Accumulation of amyloid-beta (A beta) into amyloid plaques and hyperphosphorylated tau into neurofibrillary tangles (NFTs) are pathological hallmarks of Alzheimer's disease (AD). There is a significant intra- and inter-individual variability in the morphology and conformation of A beta aggregates, which may account in part for the extensive clinical and pathophysiological heterogeneity observed in AD. In this study, we sought to identify an array of fluorescent dyes to specifically probe A beta aggregates, in an effort to address their diversity. We screened a small library of fluorescent probes and identified three benzothiazole-coumarin derivatives that stained both vascular and parenchymal A beta deposits in AD brain sections. The set of these three dyes allowed the visualization of A beta deposits in three different colors (blue, green and far-red). Importantly, two of these dyes specifically stained A beta deposits with no apparent staining of hyperphosphorylated tau or alpha-synuclein deposits. Furthermore, this set of dyes demonstrated differential interactions with distinct types of A beta deposits present in the same subject. A beta aggregate-specific dyes identified in this study have the potential to be further developed into A beta imaging probes for the diagnosis of AD. In addition, the far-red dye we identified in this study may serve as an imaging probe for small animal imaging of A beta pathology. Finally, these dyes in combination may help us advance our understanding of the relation between the various A beta deposits and the clinical diversity observed in AD.