97 TSPO in neurodegeneration EAE (Table S5), as antemortem MRI assessments in these animals allow for identification of acute lesions which are highly inflammatory. We previously defined TSPO cellular expression in MS16,71. HLA-DR+ microglia expressing TSPO were increased up to 14-fold in active lesions compared to control71, and these microglia colocalised with CD68 and had lost homeostatic markers P2RY12 and TMEM119, indicating an activated microglial state16. Here we quantified individual cellular TSPO expression in both microglia and astrocytes by comparing cells in active white matter lesions to white matter from control subjects. Consistent with the human data from AD and ALS, there was no difference in TSPO expression in individual microglia or astrocytes in MS compared to control tissue (Fig. 6a-c). We next investigated the relative levels of TSPO expression (Fig. 6d-l) in microglia and astrocytes in acute EAE (aEAE), a commonly used experimental mouse model of MS21,52. Neurodegenerative diseases typically occur in old age, whereas aEAE and the AD and ALS relevant rodent models described above are induced in young mice. As age might affect TSPO regulation72, we also investigated TSPO expression in progressive EAE (PEAE), a model where the pathology is induced in aged mice (12 months). Increases in numbers of both microglia and astrocytes were observed in aEAE as well as in PEAE mice compared to their respective young and old control groups (Fig. 6f,g). Similarly, increases were observed in the number of TSPO+ microglia and TSPO+ astrocytes in both aEAE and PEAE relative to their respective controls (Fig. 6h-j). When comparing the young control mice (aEAE controls) with the old control mice (PEAE controls), no differences were observed in microglial and TSPO+ microglial density (Fig. 6f,i). Similarly, there was no difference in density of astrocytes or TSPO+ astrocytes between these two control groups (Fig. 6g,j). To investigate individual cellular TSPO expression, TSPO+ area was measured in microglia and astrocytes. Individual microglia expressed 3-fold greater TSPO and 2-fold greater TSPO in aEAE and PEAE respectively, relative to their control groups. The individual cellular TSPO expression was not higher in microglia from young mice relative to old mice. Again, as with the SOD1G93A, AppNL-G-F, and TAUP301S mice, individual cellular TSPO expression within astrocytes was unchanged. Finally, we investigated TSPO expression in EAE induced in the common marmoset (Callithus jacchus) (Fig. S4, Fig. 6m-o), a non-human primate which, like humans, lacks the AP1 binding site in the core promoter region of TSPO. Both the neural architecture and the immune system of the marmoset are more similar to humans than are those of the mouse73-75. Marmoset EAE therefore has features of the human disease which are not seen in mouse EAE, such as perivenular white matter lesions identifiable by MRI, B cell infiltration and CD8+ T cell involvement. Marmosets were scanned with MRI biweekly, which allowed the ages of lesions to be determined and the identification of acute lesions including pro-inflammatory microglia. In acute and subacute lesions, there was an increase of up to 27-fold in the density of TSPO+ microglia relative to control (Fig. S4a-c) and these microglia bore the hallmarks of pro-inflammatory activation. However, TSPO expression in individual microglia, here defined as the percentage of TSPO+ pixels using immunofluorescence, was not increased in acute or subacute lesions relative to control (Fig. 6o).
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