The novel sphingolipids cP1P and P1P attenuate neuroinflammation and enhance S1PR1/Akt/mTOR signaling to mitigate cognitive decline in an Alzheimer’s disease mouse model

The findings demonstrate that administration of S1P analogs cP1P and P1P at 0.1 mg/kg and 1 mg/kg significantly reduced Aβ burden by inhibiting the amyloidogenic pathway and decreasing hyperphosphorylated tau protein levels in the mouse brain. Additionally, cP1P and P1P inhibited glial cell activation, as indicated by reduced GFAP and Iba-1 expression, and modulated neuroinflammatory markers, including p-NF-κB, TNF-α, and IL-1β. Furthermore, they regulated S1PR1-mediated Akt/mTOR signaling while preserving mitochondrial function by decreasing the expression levels of p-JNK, Caspase-3, and PARP-1. Moreover, the cP1P and P1P effectively restored synaptic markers such as PSD-95, SNAP-25, and Syntaxin, and significantly improved behavioral outcomes in the Aβ-treated mice. In vitro, results also demonstrated that the novel cP1P and P1P enhanced cell viability against Aβ toxicity.