Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in
Alzheimer’s disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated
in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging
using the TSPO tracer [11C]-R-PK11195 has been challenging due to the limitations of the ligand. In
this study, we aimed to evaluate the new TSPO tracer [11C]PBR28 as a marker for microglial
activation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired following
intravenous administration of [11C]PBR28 in 6 month old 5XFAD mice and in wild-type controls.
Autoradiography with [3H]PBR28 was carried out in the same brains to further confirm the
distribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brain
sections of the same mice to evaluate the co-localization of TSPO with microglia. PET imaging
revealed that brain uptake of [11C]PBR28 in 5XFAD mice was increased compared with control mice.
Moreover, binding of [3H]PBR28, measured by autoradiography, was enriched in cortical and
hippocampal brain regions, coinciding with the positive staining of the microglial marker Iba-1 and
amyloid deposits in the same areas. Furthermore, double-staining using antibodies against TSPO
demonstrated co-localization of TSPO with microglia and not with astrocytes in 5XFAD mice and
human post-mortem AD brains. Our data provide support of the suitability of [11C]PBR28 as a tool for
in vivo monitoring of microglial activation and assessment of treatment response in future studies
using animal models of AD.