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Updated: Jun 24, 2026
Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques
Published on: June 1, 2016
Visualization of brain amyloid and microglial activation in mouse models of Alzheimer's disease
1Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan. mhiguchi@nirs.go.jp
Objectives:
Microglial overactivation, which is secondary to abnormalities of amyloid-beta peptide (Abeta) and tau proteins in the pathogenic cascade leading to onset of Alzheimer's disease (AD), accelerates tau pathology, according to our recent observations using mouse models of tauopathies, and this positive feedback results in formation of a vicious cycle between upstream and downstream processes, potentially hampering effective suppression of the entire cascade by anti-amyloid treatments. This motivates our present work aimed at dual monitoring of amyloidosis and microgliosis in living animal models of AD, toward therapeutic regulation of these two processes capable of halting the self-perpetuating cycle.
Methods:
Transgenic mice expressing mutant amyloid precursor protein (APP23 mice) was examined by high-resolution positron emission tomography (PET) after administration of amyloid probe, Pittsburg Compound B (PIB) synthesized with high specific radioactivity (SA). Microglial activation in these mice was also imaged by PET and specific tracer, [(18)F]fluoroethyl-DAA1106.
Results:
Progressive amyloidosis in APP23 mice was visualized by PET and high-SA PIB. In vitro assays revealed preferential binding of PIB to N-terminally modified Abeta, Abeta(N3pE). As levels of this Abeta subspecies in model mice are lower than those in AD patients, our findings plausibly explain advantages of high-SA tracers in sensitive detection of mouse amyloid. Near-simultaneous monitoring of amyloid removal and microgliosis in APP23 mice following injection of anti-Abeta antibody demonstrated positive correlation between levels of initially existing amyloid and antibody-induced microglial activation, suggesting the possibility of microglial overactivation in immunotherapy for subjects with abundant amyloid.
Conclusions:
The present animal imaging system would substantially facilitate establishment of a safe and effective therapeutic strategy targeting multiple key processes in the AD pathogenesis.
Insights
This study developed a dual imaging system to monitor amyloid and microglial activation in Alzheimer's disease (AD) mouse models. This approach helps understand the vicious cycle in AD pathogenesis and develop safer immunotherapies.
Area of Science:
- Neuroscience
- Biomedical Imaging
- Pharmacology
Background:
- Microglial overactivation exacerbates tau pathology in Alzheimer's disease (AD).
- A vicious cycle exists between amyloid-beta (Abeta) and tau pathology, potentially limiting anti-amyloid treatments.
- Dual monitoring of amyloidosis and microgliosis is crucial for therapeutic intervention in AD.
Purpose of the Study:
- To develop and validate a dual-imaging system for simultaneous monitoring of amyloidosis and microgliosis in living AD mouse models.
- To investigate the relationship between amyloid levels and microglial activation during immunotherapy.
- To facilitate the development of safe and effective therapeutic strategies for AD.
Main Methods:
- High-resolution positron emission tomography (PET) was used to image amyloidosis with high-specific-radioactivity Pittsburg Compound B (PIB).
- Microglial activation was simultaneously imaged using PET and a specific tracer, [(18)F]fluoroethyl-DAA1106.
- In vitro assays identified PIB's preferential binding to Abeta(N3pE).
Main Results:
- PET imaging successfully visualized progressive amyloidosis in APP23 mice.
- High-specific-radioactivity PIB enabled sensitive detection of mouse amyloid, particularly Abeta(N3pE).
- A positive correlation was observed between initial amyloid levels and antibody-induced microglial activation, indicating potential overactivation during immunotherapy.
Conclusions:
- The developed dual-imaging system aids in establishing safe and effective therapeutic strategies for AD.
- Understanding the interplay between amyloid and microgliosis is key to halting AD progression.
- This system supports the development of targeted AD therapies by monitoring multiple pathological processes.
