PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET

Venneti, Sriram; Lopresti, Brian J.; Wang, Guoji; Hamilton, Ronald L.; Mathis, Chester A.; Klunk, William E.; Apte, Udayan M.; Wiley, Clayton A.

doi:10.1016/j.neurobiolaging.2007.11.005

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Volume 30, Issue 8 , Pages 1217-1226, August 2009

PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET

Sriram Venneti
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Brian J. Lopresti
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Guoji Wang
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Ronald L. Hamilton
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Chester A. Mathis
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
William E. Klunk
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Udayan M. Apte
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Clayton A. Wiley
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Corresponding author at: Presbyterian University Hospital, Neuropathology Division, 200 Lothrop Street A515, Pittsburgh, PA 15213, USA. Tel.: +1 412 647 0765; fax: +1 412 647 5602.

Received 14 July 2007; received in revised form 26 October 2007; accepted 4 November 2007. published online 07 January 2008.

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. [³H](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 [³H](R)-PK11195 binding and [¹¹C](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.

Keywords: Alzheimer's disease, Microglia, PET, PK11195, Peripheral benzodiazepine receptor, Astrocyte