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PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET
Sriram Venneti1, Brian J Lopresti, Guoji Wang
1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Abstract:
Activated microglia may promote neurodegeneration in Alzheimer's disease (AD) and may also help in amyloid clearance in immunization therapies. In vivo imaging of activated microglia using positron emission tomography (PET) could assist in defining the role of activated microglia during AD progression and therapeutics. We hypothesized that PK11195, a ligand that binds activated microglia, could label these cells in postmortem AD tissues and in vivo in an animal model of AD using PET. [(3)H](R)-PK11195 binding was significantly higher in AD frontal cortex compared to controls and correlated mainly with the abundance of immunohistochemically labeled activated microglia. With age, the brains of APP/PS1 transgenic mice showed progressive increase in [(3)H](R)-PK11195 binding and [(11)C](R)-PK11195 retention in vivo assessed using microPET, which correlated with the histopathological abundance of activated microglia. These results suggest that PK11195 binding in AD postmortem tissue and transgenic mice in vivo correlates with the extent of microglial activation and may help define the role of activated microglia in the pathogenesis and treatment of AD.
Insights
Positron emission tomography (PET) with PK11195 can visualize activated microglia in Alzheimer's disease (AD) models. This imaging method correlates microglial activation with disease progression, aiding therapeutic development.
Area of Science:
- Neuroscience
- Immunology
- Radiochemistry
Background:
- Activated microglia play a dual role in Alzheimer's disease (AD), potentially contributing to neurodegeneration while aiding amyloid clearance.
- In vivo imaging of activated microglia is crucial for understanding their role in AD progression and therapeutic responses.
Purpose of the Study:
- To investigate the utility of PK11195, a ligand for activated microglia, for imaging these cells in postmortem AD tissues and in vivo using positron emission tomography (PET).
- To correlate PK11195 binding with the extent of microglial activation and neuropathological features in AD.
Main Methods:
- In vitro binding assays using [(3)H](R)-PK11195 on postmortem human AD brain tissue.
- In vivo microPET imaging in APP/PS1 transgenic mice, a model of AD, using [(11)C](R)-PK11195.
- Correlation of radioligand binding with immunohistochemical analysis of activated microglia.
Main Results:
- [(3)H](R)-PK11195 binding was significantly elevated in the frontal cortex of AD patients compared to controls, correlating with microglial abundance.
- APP/PS1 transgenic mice exhibited age-dependent increases in [(3)H](R)-PK11195 binding and [(11)C](R)-PK11195 retention, mirroring increased microglial activation.
- In vivo and postmortem PK11195 binding strongly correlated with the histopathological assessment of activated microglia.
Conclusions:
- PK11195 serves as a reliable PET imaging agent for quantifying microglial activation in Alzheimer's disease.
- This imaging approach can help elucidate the role of activated microglia in AD pathogenesis and evaluate the efficacy of immunotherapies targeting these cells.
