title: TSPO in a murine model of Sandhoff disease: presymptomatic marker of neurodegeneration and disease pathophysiology.
abstract: Translocator protein (18 kDa), formerly known as the peripheral benzodiazepine receptor (PBR), has been extensively used as a biomarker of active brain disease and neuroinflammation. TSPO expression increases dramatically in glial cells, particularly in microglia and astrocytes, as a result of brain injury, and this phenomenon is a component of the hallmark response of the brain to injury. In this study, we used a mouse model of Sandhoff disease (SD) to assess the longitudinal expression of TSPO as a function of disease progression and its relationship to behavioral and neuropathological endpoints. Focusing on the presymptomatic period of the disease, we used ex vivo [(3)H]DPA-713 quantitative autoradiography and in vivo [(125)I]IodoDPA-713 small animal SPECT imaging to show that brain TSPO levels markedly increase prior to physical and behavioral manifestation of disease. We further show that TSPO upregulation coincides with early neuronal GM2 ganglioside aggregation and is associated with ongoing neurodegeneration and activation of both microglia and astrocytes. In brain regions with increased TSPO levels, there is a differential pattern of glial cell activation with astrocytes being activated earlier than microglia during the progression of disease. Immunofluorescent confocal imaging confirmed that TSPO colocalizes with both microglia and astrocyte markers, but the glial source of the TSPO response differs by brain region and age in SD mice. Notably, TSPO colocalization with the astrocyte marker GFAP was greater than with the microglia marker, Mac-1. Taken together, our findings have significant implications for understanding TSPO glial cell biology and for detecting neurodegeneration prior to clinical expression of disease.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Meredith K
authors.initials: MK
authors.lastname: Loth
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McGlothan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address: trg2113@cumc.columbia.edu.
authors.forename: Tomás R
authors.initials: TR
authors.lastname: Guilarte
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D020143:Gangliosidoses, GM2 / Q000378:metabolism; D008137:Longitudinal Studies; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000502:physiology; D009410:Nerve Degeneration / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D062706:Prodromal Symptoms; D018079:Receptors, GABA / Q000378:metabolism*; D012497:Sandhoff Disease / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D015415:Biomarkers; C463819:Bzrp protein, mouse; D018079:Receptors, GABA
keywords: Astrocytes; Biomarker; Microglia; Neurodegeneration; Sandhoff disease; TSPO; Translocator protein 18kDa