TSPO contributes to neuropathology and cognitive deficits in Alzheimer’s disease

Article Article scientifique Article TSPO contributes to neuropathology and cognitive deficits in Alzheimer’s disease eng 2025-10-28 author Ceyzeriat Kelly CIBM Center for Biomedical Imaging, Geneva, Switzerland. 910236 Centre d'imagerie bio-médicale (CIBM) author Badina Aurélien Matthieu Department of Psychiatry, University of Geneva, Geneva, Switzerland. 960813 Département de psychiatrie (PSYAT) author Abjean Laurène Department of Psychiatry, University of Geneva, Geneva, Switzerland.,Department of Psychiatry, University Hospitals of Geneva, Avenue de La Roseraie, 64, Geneva, 1205, Switzerland. 413354 Département de psychiatrie (PSYAT) author Meyer Léa Department of Psychiatry, University of Geneva, Geneva, Switzerland. 924126 author Bouteldja Farha Department of Psychiatry, University of Geneva, Geneva, Switzerland. 919645 author Balkota Marta Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. 975973 Département de physiologie cellulaire et métabolisme (PHYME) author Amosse Quentin 0000-0002-5553-9594 Department of Psychiatry, University of Geneva, Geneva, Switzerland. 934939 author Prudhomme Oriane Naïs Department of Psychiatry, University of Geneva, Geneva, Switzerland. 409515 author Middleton Ryan J Australian Nuclear Science and Technology Organisation (ANSTO), Sydney, Australia. author Liu Guo-Jun Australian Nuclear Science and Technology Organisation (ANSTO), Sydney, Australia.,Brain and Mind Centre, Medical Imaging Science, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. author Banati Richard B Australian Nuclear Science and Technology Organisation (ANSTO), Sydney, Australia.,Brain and Mind Centre, Medical Imaging Science, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.,Santuario Accademico S. Giovanni D'Andorno, Casa Alpina 'Principessa Laetitia', Frazione Bele, Campiglia Cervo, 13812, Italy. author Zilli Thomas Faculty of Biomedical Sciences, Università Della Svizzera Italiana, Lugano, Switzerland.,Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Radiation Oncology, Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland. 791833 Département de radiologie et informatique médicale (RADIO) author Lathuilière Aurélien 0000-0002-5191-5214 Department of Rehabilitation and Geriatrics, Memory Center, Geneva University Hospital and University of Geneva, Geneva, Switzerland. 557604 dept de réadaptation et gériatrie (MIGRG) Aurélien Lathuiliere author Owen David Department of Brain Sciences, Imperial College London, London, UK.,UK Dementia Research Institute at Imperial College London, London, UK. author Maechler Pierre 0000-0002-2005-1433 Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. 76515 Département de physiologie cellulaire et métabolisme (PHYME) author Garibotto Valentina 0000-0003-2422-698X Diagnostic Department, Division of Nuclear Medicine, University Hospitals and University of Geneva, Geneva, Switzerland. 704817 Département de radiologie et informatique médicale (RADIO) author Tsartsalis Stergios 0000-0002-6565-6313 Department of Psychiatry, University of Geneva, Geneva, Switzerland.,Department of Psychiatry, University Hospitals of Geneva, Avenue de La Roseraie, 64, Geneva, 1205, Switzerland. 782369 Département de psychiatrie (PSYAT) author Millet Philippe 0000-0002-5803-0478 Department of Psychiatry, University of Geneva, Geneva, Switzerland.,Department of Psychiatry, University Hospitals of Geneva, Avenue de La Roseraie, 64, Geneva, 1205, Switzerland. 668343 Département de psychiatrie (PSYAT) author Tournier Benjamin Department of Psychiatry, University of Geneva, Geneva, Switzerland. benjamin.tournier@hug.ch.,Department of Psychiatry, University Hospitals of Geneva, Avenue de La Roseraie, 64, Geneva, 1205, Switzerland. benjamin.tournier@hug.ch. 705309 Département de psychiatrie (PSYAT) 248 10.1186/s12974-025-03583-4 41152868 1742-2094 PMC12570730 https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-025-03583-4 The 18kDa translocator protein (TSPO) is increased in neurodegenerative diseases. In Alzheimer's disease (AD) animal models, TSPO's upregulation is detected first in astrocytes, then in microglia. However, the role of TSPO in the pathophysiology and symptoms characteristic of the disease remains unknown. In the human postmortem hippocampus, we show here that TSPO correlated positively with reactive astrocyte-associated genes and negatively with genes involved in glycolytic pathways. In addition, we observed that TSPO deletion in 3 × TgAD mice reversed the reduction in glucose uptake and reduced astrocyte reactivity. We observed a decrease of poorly and highly aggregated forms of Tau (-44% and -82%, respectively) and Aβ42 (-25% and -95%, respectively) at 9 months of age. In 5 × FAD mice, we confirmed the association between TSPO, astrocyte reactivity and Aβ. Functionally, Tau over-expression in the hippocampus induced a memory decline in WT animals, prevented in TSPO<sup>-/-</sup> mice. Altogether, these data demonstrate that TSPO plays an important role in the active progression of AD. This identifies TSPO as a potential therapeutic target and highlights the importance of astrocyte metabolism in the pathogenesis of the disease. 3 × TgAD Alzheimer’s disease Astrocytes Hippocampus TSPO Dewey 616.89 Dewey 612 Dewey 616.0757 Dewey 618.97 Swiss National Science Foundation Molecular Imaging of Neuroinflammation in Bipolar Disorder: a Translational Validation of the TSPO Quantification Methodology 184713 CH Swiss National Science Foundation TSPO in astrocytes and microglia: role and therapeutic potential in Alzheimer’s disease. 212322 CH Swiss National Science Foundation An integrated multi-organ analysis of glutamate dehydrogenase 192486 CH Swiss National Science Foundation A translational assessment of central nervous system innate immunity to identify how social support and oxytocin interact to protect against Alzheimer’s disease 223414 CH 60 Département de psychiatrie 225 134 Département de physiologie cellulaire et métabolisme 21C 65 Département de réadaptation et gériatrie 22B 62 Département de radiologie et informatique médicale 227 false 1221 Neuroimagerie moléculaire en psychiatrie 983 1451 Recherche translationnelle en neurodégénérescence 1068 402 Mitochondries et métabolisme énergétique 671 1222 Laboratoire de neuroimagerie et de traceurs moléculaires innovants 984 Journal of neuroinflammation 22 1 903d71e3-15af-40fb-adf9-ba207ca6181f Article (Published version) Public Article_scientifique_from_crossref.pdf 15164084 application/pdf CC BY-4.0 a345cb76f6754ba0aa0020f4281ce19def94992a94b80266460a3c8bfe78c3f0 18eb6c12-7723-497b-80c5-dadf70eb5ecf Supplemental data Public 12974_2025_3583_MOESM1_ESM.pdf 5886383 application/pdf ccb47a66ca64d333cd60ee91beb894fa90a2a477aae6cdadcce75a2437f6ec35 openAccess Faculté de médecine / Section de médecine clinique / Département de psychiatrie Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département de réadaptation et gériatrie Faculté de médecine / Section de médecine clinique / Département de radiologie et informatique médicale

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TSPO contributes to neuropathology and cognitive deficits in Alzheimer’s disease	Journal of neuroinflammation	2025	43	25
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