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^-/- 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.