Esketamine induces tripartite motif-containing protein 24 to improve cognitive dysfunction in Alzheimer's disease.

Esketamine improved spatial learning and memory in triple transgenic Alzheimer's disease (3xTg-AD) mice. The drug increased expression of TRIM24, which activated the PI3K/AKT pathway in the hippocampus. Depleting TRIM24 reversed these cognitive benefits and blocked PI3K/AKT signaling. Esketamine also reduced neuroinflammation—lowering pro-inflammatory molecules, GFAP, and p-Tau—but this effect was lost when TRIM24 was knocked down. Blocking the PI3K/AKT pathway worsened cognitive deficits and inflammation. Thus, esketamine may counteract Alzheimer's-related cognitive decline by suppressing neuroinflammation through the TRIM24/PI3K/AKT axis.

Study at a glance

Abstract

Esketamine has been revealed to improve cognitive impairments under different conditions, while its function in Alzheimer's disease (AD) has not been well characterized. We expounded the effects and detailed mechanism of esketamine in triple transgenic AD (3xTg-AD) mice in the present study. The impaired spatial learning and memory retention of 3xTg-AD mice were ameliorated by esketamine, whereas tripartite motif-containing protein 24 (TRIM24) depletion reversed the ameliorative effects of esketamine in 3xTg-AD mice. Esketamine elevated the extent of PI3K and AKT phosphorylation in the hippocampus by promoting TRIM24 expression, and knockdown of TRIM24 impaired the PI3K/AKT pathway. AD-like mice had increased expression of pro-inflammatory molecules and elevated expression of GFAP and p-Tau. Esketamine reduced inflammation, but its therapeutic effect was reversed by TRIM24 knockdown. The PI3K/AKT pathway blockage exacerbated cognitive deficits and neuroinflammatory responses in mice. Thus, esketamine has the potential to improve the cognitive and memory functions of 3xTg-AD mice by repressing neuroinflammation by activating TRIM24 and the downstream PI3K/AKT pathway.