Neuronal Cholesterol Deficiency Mediated by Astrocytic SREBP2 Downregulation Leads to Postoperative Cognitive Dysfunction Through Impairment of Hippocampal Synaptic Plasticity and Excitatory Synaptic Transmission

ABSTRACT Postoperative cognitive dysfunction (POCD) negatively impacts prognosis; however, the underlying mechanisms remain unclear. We demonstrated that tibial fracture surgery led to cognitive dysfunction in 18‐month‐old mice, concomitant with a reduction in hippocampal levels of cholesterol and its key metabolite 24‐hydroxycholesterol (24‐OHC). Clinically, reduced blood 24‐OHC levels were associated with cognitive decline in elderly surgery patients. Mechanistically, downregulation of sterol regulatory element‐binding protein 2 (SREBP2) in reactive astrocytes of the hippocampal dorsal CA1 (dCA1) region was an important cause of postoperative cholesterol deficiency, which in turn impaired synaptic plasticity and excitatory synaptic transmission; furthermore, this deficit could be rescued by direct cholesterol replenishment in the dCA1. Importantly, we established multiple effective therapeutic strategies—astrocyte‐specific SREBP2 overexpression, chemogenetic suppression of reactive astrocytes, and minocycline administration—all of which effectively reversed surgery‐induced cholesterol loss, alleviated synaptic dysfunction, and ultimately improved cognitive performance. Taken together, our findings not only position astrocytic SREBP2 as a promising therapeutic target for POCD but also highlight the potential diagnostic value of monitoring brain cholesterol metabolism, though this requires validation in larger longitudinal cohorts.