The microglial translocator protein (TSPO) in Alzheimer's disease reflects a phagocytic phenotype.

Abstract

Translocator protein (TSPO) is a mitochondrial protein expressed by microglia, ligands for which are used as a marker of neuroinflammation in PET studies of Alzheimer's disease (AD). We previously showed increasing TSPO load in the cerebral cortex with AD progression, consistent with TSPO PET scan findings. Here, we aim to characterise the microglial phenotype associated with TSPO expression to aid interpretation of the signal generated by TSPO ligands in patients. Human post-mortem sections of temporal lobe (TL) and cerebellum (Cb) from cases classified by Braak group (0-II, III-IV, V-VI; each n = 10) were fluorescently double labelled for TSPO and microglial markers: Iba1, HLA-DR, CD68, MSR-A and CD64. Quantification was performed on scanned images using QuPath software to assess the microglial phenotype of TSPO. Qualitative analysis was also performed for TSPO with GFAP (astrocytes), CD31 (endothelial cells) and CD163 (perivascular macrophages) to characterise the cellular profile of TSPO. The percentage of CD68TSPO double-labelled cells was significantly higher than for other microglial markers in both brain regions and in all Braak stages, followed by MSR-ATSPO microglia. Iba1TSPO cells were more numerous in the cerebellum than the temporal lobe, while CD64TSPO cells were more numerous in the temporal lobe. No differences were observed for the other microglial markers. TSPO expression was also detected in endothelial cells, but not detected in astrocytes nor in perivascular macrophages. Our data suggest that TSPO is mainly related to a phagocytic profile of microglia (CD68) in human AD, potentially highlighting the ongoing neurodegeneration.

References:

• Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD et al (2017) QuPath: Open source software for digital pathology image analysis. Sci Rep 7:16878. 10.1038/s41598-017-17204-5
• Boche D, Gordon MN (2021) Diversity of transcriptomic microglial phenotypes in aging and Alzheimer’s disease. Alzheimers Dement. 10.1002/alz.12389
• Boche D, Nicoll JAR (2020) Invited review - Understanding cause and effect in Alzheimer’s pathophysiology: Implications for clinical trials. Neuropathol Appl Neurobiol 46:623–640. 10.1111/nan.12642
• Butovsky O, Weiner HL (2018) Microglial signatures and their role in health and disease. Nat Rev Neurosci 19:622–635. 10.1038/s41583-018-0057-5
• Christensen A, Pike CJ (2018) TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice. Neurosci Lett 683:7–12. 10.1016/j.neulet.2018.06.029