A lifetime window into lipid dynamics in Alzheimer's disease

초록

Aberrant lipid metabolism is increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet its spatiotemporal visualization within the brain microenvironment remains a formidable challenge. Herein, we report a molecular engineering strategy that enhances the zwitterionic-neutral isomerization sensitivity of the rhodol scaffold, yielding a new generation of isomerization-driven rhodol fluorophores with finely tunable fluorescence lifetimes. Through stepwise heteroatom and heterocyclic modulation (P-SRd, P-PRd, P-SiRd, and Q-SiRd), the isomerization efficiency and charge-transfer distance were systematically optimized, as supported by theoretical calculations. Among them, the best-performing candidate, Q-SiRd, exhibited exceptional responsiveness to micro-polarity fluctuations, enabling fluorescence lifetime imaging (FLIM) of lipid dynamics in living cells and AD mouse brain tissues. Q-SiRd precisely monitored polarity variations within lysosomes and lipid droplets under drug stimulation and during cellular senescence, and further unveiled microenvironmental remodeling associated with AD progression. The key findings include: (i) observation of lipid droplet formation within regions of A beta 42 plaque deposition; (ii) lipid droplet accumulation adjacent to these plaques induced notable increase in fluorescence lifetime, indicative of decreased local micro-polarity; (iii) progressive increases in fluorescence lifetime were observed in the hippocampus and cerebral cortex as the disease advanced. These findings establish Q-SiRd as a powerful lifetime-resolved probe for mapping lipid metabolic alterations, advancing our understanding of organelle interplay and metabolic remodeling in neurodegenerative disorders.

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