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

Abstract

Background: Alzheimer's disease (AD) is the leading cause of dementia, characterized by the accumulation of amyloid-βeta (Aβ) peptides and hyperphosphorylated tau protein. Altered sphingosine 1-phosphate (S1P) metabolism is associated with abnormal Aβ peptide accumulation in the brain. S1P receptors are increasingly being targeted for modulating the neuroinflammatory process in AD. Methods: Wild-type male C57BL/6J mice were administered Aβ to induce the pathological state. The study included four experimental groups: (1) Control group (saline-treated), (2) Aβ group (Aβ + saline-treated), (3) Aβ + cP1P group (Aβ + cP1P at doses of 0.1 mg/kg and 1 mg/kg), and (4) Aβ+ P1P group (Aβ + P1P at doses of 0.1 mg/kg and 1 mg/kg). Behavioral experiments were conducted to assess cognitive and memory functions. Additionally, western blotting and confocal microscopy were performed to investigate molecular and cellular changes. Results: 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.