Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
Marta Vicente‐Rodríguez, Renzo Mancuso, Alba Peris-Yague, Camilla Simmons, Dominika Wlazly, Amber Dickinson, Andy Foster, Clare Knight, Claire A. Leckey, Paul T. Morgan, Angharad R. Morgan, Caroline O’Hagan, Samuel Touchard, Shahid A. Khan, Phil Murphy, Christine A. Parker, Jai Patel, Jill Richardson, Paul D. Acton, Nigel Austin, Anindya Bhattacharya, Nick Carruthers, Peter de Boer, Wayne C. Drevets, John Isaac, Declan N.C. Jones, John A. Kemp, Hartmuth C. Kolb, Jeff Nye, Gayle Wittenberg, Gareth J. Barker, Anna Bogdanova, Heidi Byrom, Annamaria Cattaneo, Daniela Enache, Antony D. Gee, Caitlin Hastings, Melisa Kose, Giulia Lombardo, Nicole Mariani, Anna McLaughlin, Valeria Mondelli, Maria Antonietta Nettis, Naghmeh Nikkheslat, Carmine M. Pariante, Karen Randall, Julia Schubert, Luca Sforzini, Hannah Sheridan, Nisha Singh, Vicky Van Loo, Mattia Veronese, Toby Wood, Courtney Worrell, Zuzanna Zajkowska, Brian Campbell, Jan Egebjerg, Hans Eriksson, François Gastambide, Karen Husted Adams, Ross Jeggo, Thomas Möeller, Bob Nelson, Niels Plath, C. Thomsen, Jan Pederson, Stevin H. Zorn, Catherine Deith, Scott Farmer, John McClean, Andrew McPherson, Nagore Penandes, Paul Scouller, Murray Sutherland, Mary-Jane Attenburrow, Jithen Benjamin, Helen Jones, Fran Mada, Akintayo Oladejo, Katy D. Smith, Rita J. Balice‐Gordon, Brendon Binneman, James M. Duerr, Terence Fullerton, Veeru Goli, Zoë A. Hughes, Justin R. Piro, Tarek A. Samad, Jonathan Sporn, Liz Hoskins, Charmaine Kohn, Lauren Wilcock, Franklin I. Aigbirhio, Junaid Bhatti, Edward T. Bullmore, Sam Chamberlain, Marta Correia, Anna Crofts, Tim D. Fryer, Martin J. Graves
Abstract
Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or a secondary outcome. For that reason, either as diagnostic tools or to monitor progression and/or pharmacological interventions, there is a need for robust biomarkers of neuroinflammation in the brain. Mitochondrial TSPO (18 kDa Translocator protein) is one of few available biomarkers of neuroinflammation for which there are clinically available PET imaging agents. In this study, we further characterised neuroinflammation in a mouse model of prion-induced chronic neurodegeneration (ME7) including a pharmacological intervention via a CSF1R inhibitor. This was achieved by autoradiographic binding of the second-generation TSPO tracer, [3H]PBR28, along with a more comprehensive examination of the cellular contributors to the TSPO signal changes by immunohistochemistry. We observed regional increases of TSPO in the ME7 mouse brains, particularly in the hippocampus, cortex and thalamus. This increased TSPO signal was detected in the cells of microglia/macrophage lineage as well as in astrocytes, endothelial cells and neurons. Importantly, we show that the selective CSF1R inhibitor, JNJ-40346527 (JNJ527), attenuated the disease-dependent increase in TSPO signal, particularly in the dentate gyrus of the hippocampus, where JNJ527 attenuated the number of Iba1+ microglia and neurons, but not GFAP+ astrocytes or endothelial cells. These findings suggest that [3H]PBR28 quantitative autoradiography in combination with immunohistochemistry are important translational tools for detecting and quantifying neuroinflammation, and its treatments, in neurodegenerative disease. Furthermore, we demonstrate that although TSPO overexpression in the ME7 brains was driven by various cell types, the therapeutic effect of the CSF1R inhibitor was primarily to modulate TSPO expression in microglia and neurons, which identifies an important route of biological action of this particular CSF1R inhibitor and provides an example of a cell-specific effect of this type of therapeutic agent on the neuroinflammatory process.