Visualizing Tau Tangles in AD Retina with a BODIPY‐based Fluorescent Ligand

Abstract Background Alzheimer’s disease (AD) is a neurodegenerative disease responsible for most cases of senile dementia. Despite numerous studies, there are no effective therapies or significant progress in symptom progression. To develop a therapeutic strategy, research has focused on accurate diagnostic methods. Coupled units of hyperphosphorylated protein (P‐Tau) and total‐Tau monomers (t‐Tau) are reliable biomarkers for AD. Early identification of neurofibrillary tangles (NFTs) in retinal tissue is a promising diagnostic tool. The development of highly specific Tau fluorophores has been achieved through the construction of a computational model of TAU oligomers. Methods The construction of the highly specific Tau fluorophore BT‐1 (Soloperto et al., 2021) consisting of a BODIPY‐based probe showed excellent photophysical properties and high selectivity allowing in vitro imaging of hyperphosphorylated tau protein filaments with minimal background noise. Delivery to living iPSC derived retinal cells was achieved by identifying a class of delivery cargoes among ferritin proteins, natural nanocages that can embed small molecules and enter human cells expressing the transferrin receptor. Results BT‐1 colocalizes with phosphorylated and oligomeric tau in AD retinal slices. Loading the ferritin nanocage with the fluorescent probe BT‐1 generated a unique formulation for the delivery of the fluorescent probe to retinal tissue. Conclusion The use of ferritin nanocages loaded with the fluorescent probe BT‐1 provides a promising method for the specific identification of NFTs in retinal tissue for the clinical diagnosis of AD. The encapsulation of other substrates in ferritin nanocages has potential applications in nanomedicine.