Methionine restriction inhibits the TGF-β1/CCN2/NF-κB pathway to attenuate astrocyte inflammation and cognitive impairment in the APP/PS1 mice.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by cognitive impairment. Astrocytes are involved in AD by clearing amyloid-beta peptide (Aβ) and regulating neuroinflammation. In recent years, methionine restriction (MR) has attracted increasing attention for its benefits in extending lifespan and inhibiting tumor growth. However, the molecular mechanisms underlying the alleviation of astrocyte-mediated neuroinflammation by MR to delay the progression of AD are not well understood. This study determined the existence of the methionine cycle in astrocytes, which was disorganized in AD models. After 4 months of MR dietary intervention, APP/PS1 mice showed improved cognitive function, reduced neuronal loss, decreased Aβ plaque burden, increased dendritic spine density, and lower astrocyte abnormal activation. RNA sequencing of APP/PS1 mouse hippocampal tissue revealed that MR reduced neuroinflammation by downregulating the TGF-β1/CCN2 signaling pathway. Both in vitro and in vivo experiments demonstrated that MR down-regulated CCN2 expression, which in turn reduced the level of neuroinflammation. Moreover, CCN2 downregulation was accompanied by suppression of the NF-κB signaling pathway. This study showed that MR reduced the inflammation mediated by astrocytes and cognitive decline in AD by blocking the TGF-β1/CCN2/NF-κB signaling pathway.