127 TSPO expression in healthy and diseased brain AHL A B C D E F G H I J K L M N O P Schizophrenia FTD-TDP-PGN AHL PML FTD-TDP-PGN VWM Acute stroke PML Acute stroke PML FTD-FUS FTD-FUS VWM PLP/HLA-DR FXTAS FXTAS Figure 1. Cellular sources of TSPO expression in the CNS. Multiple cell origin of TSPO in the pathological human brain. Astrocytes and perivascular macrophages are positive for TSPO in acute hemorrhagic leukoencephalopathy (A, B). At the site of injury, acute stroke cells express TSPO in two separate cases (C, D). A schizophrenia patient with TSPO+ microglia and endothelial cells in the anterior cingulate cortex (E). Lesions in progressive multifocal leukoencephalopathy are abundant with TSPO in microglia, macrophages, and astrocytes in the white and gray matter (F, G, H). Patients with frontotemporal dementia with mutations for TDP, proganulin, and FUS have a macrophage-like cells expressing TSPO in the white matter and in perivascular spaces (I, J, K, L). Macrophages in vanishing white matter express TSPO throughout the white matter areas in the brain parenchyma (M, N). Fragile X-associated tremor/ataxia syndrome has TSPO+ astrocytes in the white matter and microglia in both white and gray matter (O, P). microglia, neurons, and endothelial cells and the radioligand-mediated labelling of TSPO (RTT, radioligand-treated tissues). TSPOoverexpressionwas studied in response toacuteunilateral injectionof lipopolysaccharide (LPS) or of ciliary neurotrophic factor (CNTF), in a rat model of AD and in the AD brain192,193. In all these pathological contexts, TSPO is overexpressed. However, the cellular origin of TSPO overexpression is context-dependent and cellular mechanisms leading to this increase are heterogeneous (proliferation of the cell population and/or changes in TSPO expression by each single cell). Furthermore, the involvement of endothelial TSPO binding in the overall TSPO signal is at the centre of in vivo imaging interrogations. In the case of these models of inflammation, endothelial cells contributed to basal TSPO signal but not to its increase192,193. These results potentially answer a fundamental question in the domain of in vivo imaging of neuroinflammation, i.e. regarding the necessity to take the endothelial TSPO signal into account when quantifying TSPO in vivo using PET. Still, it is important to keep in mind that
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