Visualizing Tau tangles in AD retina with BODIPY-based fluorescent ligand.

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 cell permeant peptides (CPP), natural nanocages that can embed small molecules and enter human cells. Results: BT-1 colocalizes with phosphorylated and oligomeric tau in AD retinal slices and iPSC derived retinal cells. Loading the CPP 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 CPP 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 CPP has potential applications in nanomedicine.