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In Alzheimer\u2019s disease (AD) animal models, TSPO\u2019s 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\n                    <jats:italic>postmortem<\/jats:italic>\n                    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\u2009\u00d7\u2009TgAD 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 A\u03b242 (-25% and -95%, respectively) at 9 months of age. In 5\u2009\u00d7\u2009FAD mice, we confirmed the association between TSPO, astrocyte reactivity and A\u03b2. Functionally, Tau over-expression in the hippocampus induced a memory decline in WT animals, prevented in TSPO\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1186\/s12974-025-03583-4","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T15:46:14Z","timestamp":1761666374000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["TSPO contributes to neuropathology and cognitive deficits in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"22","author":[{"given":"Kelly","family":"Ceyz\u00e9riat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lien M.","family":"Badina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurene","family":"Abjean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9a","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farha","family":"Bouteldja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Balkota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Amoss\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriane","family":"Prudhomme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J.","family":"Middleton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard B.","family":"Banati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Zilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelien","family":"Lathuiliere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Owen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Maechler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Garibotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stergios","family":"Tsartsalis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Millet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin B.","family":"Tournier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"3583_CR1","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1038\/d41586-018-05718-5","volume":"559","author":"L Drew","year":"2018","unstructured":"Drew L. 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