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Updated: Aug 5, 2026
Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Published on: June 1, 2016
Multispectral photoacoustic microscopy and NIR-II fluorescence imaging of TREM2-positive microglia in Aβ-driven
Hsuan Lo1,2, Shiying Li1,2, Jiali Chen2,3
1Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Abstract:
Monitoring microglial activation mediators remains challenging in neurodegeneration. Few imaging studies track amyloid-β (Aβ)-linked microglial dynamics across a wide field of view with high spatiotemporal resolution. Leveraging the triggering receptor expressed on myeloid cells 2 (TREM2), a pivotal Alzheimer's disease (AD) biomarker that enhances Aβ clearance while suppressing neuroinflammation, we developed a dual-modal probe, TREM2-ICG, by conjugating a TREM2-specific antibody with indocyanine green (ICG), an FDA-approved dye, for robust in vivo photoacoustic and near-infrared-II (NIR-II) fluorescence imaging. Multi-wavelength photoacoustic microscopy imaged AD pathology at 532 nm (hemoglobin, vasculature), 559 nm (Aβ probe AOI987), and 780 nm (TREM2-ICG for peri‑plaque microglia). Time-resolved NIR-II imaging (30 frames/sec) tracked Aβ-oligomer-induced microglial displacement at ∼50 µm resolution, showing a rapid chemotaxis phenomenon. Immunofluorescence-verified TREM2-microglia plaque engagement demonstrates AD pathogenesis. Overall, our multiscale photoacoustic-fluorescence imaging resolved cortex-wide Aβ-microglial interactions, combining wide-field, high-speed, and deep-penetration to overcome confocal depth and two-photon field of view limits. This enabled in vivo tracking of microglial responses to Aβ, revealing potential for investigating AD-specific mechanisms.
Insights
Researchers developed a novel dual-modal imaging probe (TREM2-ICG) to track microglial responses to amyloid-beta plaques in Alzheimer's disease (AD) models. This technique offers unprecedented spatiotemporal resolution for studying neuroinflammation in vivo.
Area of Science:
- Neuroscience
- Biomedical Imaging
- Alzheimer's Disease Research
Background:
- Monitoring microglial activation in neurodegeneration is challenging.
- Existing imaging methods lack the spatiotemporal resolution and field of view to track amyloid-beta (Aβ)-linked microglial dynamics.
- Triggering receptor expressed on myeloid cells 2 (TREM2) is a key Alzheimer's disease (AD) biomarker involved in Aβ clearance and neuroinflammation.
Purpose of the Study:
- To develop a dual-modal imaging probe for robust in vivo photoacoustic and near-infrared-II (NIR-II) fluorescence imaging of TREM2-expressing microglia.
- To track Aβ-linked microglial dynamics with high spatiotemporal resolution across a wide field of view.
- To investigate AD pathogenesis by visualizing TREM2-microglia plaque engagement and microglial responses to Aβ.
Main Methods:
- Conjugation of a TREM2-specific antibody with indocyanine green (ICG) to create the TREM2-ICG probe.
- Multi-wavelength photoacoustic microscopy (532 nm for hemoglobin, 559 nm for Aβ probe AOI987, 780 nm for TREM2-ICG).
- Time-resolved NIR-II fluorescence imaging (30 frames/sec) for tracking microglial displacement and chemotaxis.
Main Results:
- The TREM2-ICG probe enabled robust in vivo imaging of peri-plaque microglia using photoacoustic and NIR-II fluorescence modalities.
- High-speed NIR-II imaging revealed rapid, Aβ-oligomer-induced microglial displacement, demonstrating chemotaxis.
- Multiscale imaging resolved cortex-wide Aβ-microglial interactions, overcoming limitations of confocal and two-photon microscopy.
Conclusions:
- The developed dual-modal TREM2-ICG probe provides a powerful tool for in vivo tracking of microglial responses to Aβ.
- This imaging approach offers wide-field, high-speed, and deep-penetration capabilities for studying AD pathogenesis.
- The findings highlight the potential for investigating AD-specific mechanisms and therapeutic targets through advanced imaging techniques.