This paper presents Fluorescence-guided Bond-Selective Intensity Diffraction Tomography (FBS-IDT), a computational chemical microscope integrating 3D mid-infrared photothermal imaging with fluorescence imaging, to analyze intracellular tau fibrils. FBS-IDT enables chemical-specific volumetric imaging and 3D spectroscopic analysis of tau fibrils within their native cellular environment. The study demonstrates label-free volumetric chemical imaging of cells with and without tau fibrils, showing a potential correlation between lipid accumulation and tau aggregate formation. Depth-resolved mid-infrared fingerprint spectroscopy reveals the protein secondary structure of intracellular tau fibrils, achieving 3D visualization of β-sheet structures.

Jian Zhao, Lulu Jiang, Alex Matlock, Yihong Xu, Jiabei Zhu, Hongbo Zhu, Lei Tian, Benjamin Wolozin, Ji-Xin Cheng