The relevance between abnormally elevated serum ceramide and cognitive impairment in Alzheimer's disease model mice and its mechanism.

ABSTRACT

RATIONALE The plasma ceramide levels in Alzheimer's disease (AD) patients are found abnormally elevated, which is related to cognitive decline. OBJECTIVES: This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD. RESULTS: The ICR mice intracerebroventricularly injected with Aß1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3ß (GSK-3ß) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData. CONCLUSIONS: Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis.