A Polarity-Sensitive Lipid Droplet Probe Reveals Aβ Species-Dependent Lipid Droplet Remodeling in Microglia

  • ACS Sens. 2026 Jun 26;11(6):5047-5057. doi: 10.1021/acssensors.6c01055.
Panyi Hu  1  2 ,  Shuo Guo  3 ,  Youxiang Ren  4 ,  Rui Zhao  1  2 ,  Liping Su  1  2  5 ,  Jiahan Cheng  6 ,  Xiaohe Tian  1  2  7  8
Affiliations
  • 1. Department of Radiology, Huaxi MR Research Center (HMRRC), Institute of Radiology and Medical Imaging, West China Hospital of Sichuan University, Chengdu610041, Sichuan, China.
  • 2. Psychoradiology Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
  • 3. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 4. Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
  • 5. State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Sichuan University, Chengdu 610041, China.
  • 6. Institute of Thoracic Oncology and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 7. Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610000, Sichuan, China.
  • 8. Xiamen Key Lab of Psychoradiology and Neuromodulation, Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, Fujian 361000, China.
PMID: 42263671 DOI: 10.1021/acssensors.6c01055
Abstract

Microglial lipid metabolic alterations are increasingly implicated in Alzheimer's disease (AD), yet the specific β-amyloid (Aβ) species involved in lipid droplet (LD) remodeling remain unclear. Precise visualization of LD morphology in complex biological systems is limited by the availability of selective and photostable probes. Herein, we report a polarity-sensitive LD probe, BODIPY-LD, constructed with a donor-π-acceptor-π-donor (D-π-A-π-D) framework that enables hydrophobic targeting and intramolecular charge transfer (ICT)-based fluorescence activation in low-polarity environments. The probe allows high-contrast visualization and quantitative assessment of LD morphology in cells and brain tissues. Using BODIPY-LD, we observed increased LD burden in hippocampal microglia of APP/PS1 mice and systematically compared the effects of different Aβ25-35 assembly states on LD accumulation in BV2 microglia. Among monomeric, oligomeric, and fibrillar Aβ25-35 forms, the monomer-treated BV2 cells showed the most pronounced LD enrichment under our experimental conditions. This LD-rich phenotype was associated with reduced phagocytic capacity and was partially reversible upon inhibition of LD synthesis using the long-chain acyl-CoA synthetases (ACSL) inhibitor Triacsin C. Together, these findings suggest that monomeric Aβ25-35 is associated with an LD-rich microglial phenotype and impaired phagocytic function in vitro model. Beyond this biological observation, BODIPY-LD provides a useful tool for studying lipid remodeling in neuroinflammatory contexts.

Keywords
Alzheimer's disease; Aβ species; fluorescent probe; lipid droplet; microglial metabolism.
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