14-3-3γ Protects Against Postoperative Cognitive Dysfunction by Regulating Tau Thr205 Phosphorylation and Synaptic Integrity.

BACKGROUND: 14-3-3γ is implicated in neurodegeneration, yet its role in postoperative cognitive dysfunction (POCD) remains unclear. METHODS: We performed CSF proteomic profiling using the SomaScan 7K platform in the Alzheimer's Disease Neuroimaging Initiative cohort (n = 237) to identify biomarkers associated with neurodegeneration-enriched cognitive vulnerability (NECV). A prospective surgical cohort (n = 213) was used to evaluate circulating 14-3-3γ levels in relation to perioperative cognitive outcomes. Mechanistic studies were conducted using a murine surgery model, AAV-mediated gene manipulation, neuronal cultures, pharmacological intervention, and molecular dynamics simulations. RESULTS: CSF proteomics identified 14-3-3γ as a candidate biomarker associated with NECV and neurodegenerative progression. Plasma 14-3-3γ levels were associated with POCD and postoperative delirium. In mice, anesthesia and surgery reduced hippocampal 14-3-3γ expression, accompanied by increased Tau phosphorylation at Thr205 among examined sites, synaptic dysfunction, and cognitive impairment. Neuronal 14-3-3γ overexpression rescued these deficits. Mechanistically, 14-3-3γ interacted with Tau in a phosphorylation-dependent manner and regulated Tau phosphorylation homeostasis. Pharmacological stabilization of the 14-3-3γ-Tau interaction using FC-A reduced Tau Thr205 phosphorylation and improved cognition, whereas TauT205E expression diminished this rescue effect. CONCLUSIONS: 14-3-3γ represents a potential regulator of postoperative cognitive vulnerability and a candidate therapeutic target for POCD.