Esketamine induces tripartite motif-containing protein 24 to improve cognitive dysfunction in Alzheimer's disease.
Neuroscience letters – June 21, 2024
Source: PubMed
Summary
A promising breakthrough in Alzheimer's treatment shows that esketamine, a fast-acting medication, can improve memory and cognitive function. The drug works by activating TRIM24, a protein that reduces brain inflammation through the PI3K/AKT pathway. Tests in specialized Alzheimer's mice demonstrated significant improvements in learning and memory, while also decreasing harmful inflammatory responses in the brain.
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.