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

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.