Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease
Authors: Vicente-Rodríguez Marta , Mancuso Renzo , Peris-Yague Alba , Simmons Camilla ,   NIMA Consortium, Wlazly Dominika , Dickinson Amber , Foster Andy , Knight Clare , Leckey Claire , Morgan Paul , Morgan Angharad , O’Hagan Caroline , Touchard Samuel , Khan Shahid , Murphy Phil , Parker Christine , Patel Jai , Richardson Jill , Acton Paul , Austin Nigel , Bhattacharya Anindya , Carruthers Nick , de Boer Peter , Drevets Wayne , Isaac John , Jones Declan , Kemp John , Kolb Hartmuth , Nye Jeff , Wittenberg Gayle , Barker Gareth , Bogdanova Anna , Byrom Heidi , Cattaneo Annamaria , Enache Daniela , Gee Tony , Hastings Caitlin , Kose Melisa , Lombardo Giulia , Mariani Nicole , McLaughlin Anna , Mondelli Valeria , Nettis Maria , Nikkheslat Naghmeh , Pariante Carmine , Randall Karen , Schubert Julia , Sforzini Luca , Sheridan Hannah , Singh Nisha , Van Loo Vicky , Veronese Mattia , Wood Toby , Worrell Courtney , Zajkowska Zuzanna , Campbell Brian , Egebjerg Jan , Eriksson Hans , Gastambide Francois , Adams Karen Husted , Jeggo Ross , Moeller Thomas , Nelson Bob , Plath Niels , Thomsen Christian , Pederson Jan Torleif , Zorn Stevin , Deith Catherine , Farmer Scott , McClean John , McPherson Andrew , Penandes Nagore , Scouller Paul , Sutherland Murray , Attenburrow Mary Jane , Benjamin Jithen , Jones Helen , Mada Fran , Oladejo Akintayo , Smith Katy , Balice-Gordon Rita , Binneman Brendon , Duerr James , Fullerton Terence , Goli Veeru , Hughes Zoe , Piro Justin , Samad Tarek , Sporn Jonathan , Hoskins Liz , Kohn Charmaine , Wilcock Lauren , Aigbirhio Franklin , Bhatti Junaid , Bullmore Ed , Chamberlain Sam , Correia Marta , Crofts Anna , Fryer Tim , Graves Martin , Hatton Alex , Kitzbichler Manfred , Lynall Mary-Ellen , Maurice Christina , O’Donnell Ciara , Pointon Linda , Hyslop Peter St George , Turner Lorinda , Vertes Petra , Widmer Barry , Williams Guy , Cavanagh Jonathan , McColl Alison , Shaw Robin , Boddeke Erik , Baird Alison , Clare Stuart , Cowen Phil , Huang I-Shu , Hurley Sam , Nevado-Holgado Alejo , Ribe Elena , Vyas Anviti , Winchester Laura , Cleal Madeleine , Gomez-Nicola Diego , Perry Hugh , Cercignani Mara , Clarke Charlotte , Colasanti Alessandro , Harrison Neil , Murray Rosemary , O’Connor Jason , Mount Howard , Gómez-Nicola Diego , Perry V. Hugh , Turkheimer Federico , Lovestone Simon , Parker Christine A. , Cash Diana 
Published: April 2023

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.