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

ABSTRACT

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.