Deciphering the Link Between Hyperhomocysteinemia and Ceramide Metabolism in Alzheimer-Type Neurodegeneration.

Hervé Le Stunff,Kelly Meneyrol,Jean-Louis Paul,Jessica Denom,Christophe Magnan,Nadim Kassis,Nathalie Janel,Julien Véret,Céline Cruciani-Guglielmacci

doi:10.3389/fneur.2019.00807

Abstract

Aging is one of the strongest risk factor for Alzheimer's disease (AD). However, several data suggest that dyslipidemia can either contribute or serve as co-factors in AD appearance. AD could be examined as a metabolic disorder mediated by peripheral insulin resistance. Insulin resistance is associated with dyslipidemia, which results in increased hepatic ceramide generation. Hepatic steatosis induces pro-inflammatory cytokine activation which is mediated by the increased ceramides production. Ceramides levels increased in cells due to perturbation in sphingolipid metabolism and upregulated expression of enzymes involved in ceramide synthesis. Cytotoxic ceramides and related molecules generated in liver promote insulin resistance, traffic through the circulation due to injury or cell death caused by local liver inflammation, and because of their hydrophobic nature, they can cross the blood-brain barrier and thereby exert neurotoxic responses as reducing insulin signaling and increasing pro-inflammatory cytokines. These abnormalities propagate a cascade of neurodegeneration associated with oxidative stress and ceramide generation, which potentiate brain insulin resistance, apoptosis, myelin degeneration, and neuro-inflammation. Therefore, excess of toxic lipids generated in liver can cause neurodegeneration. Elevated homocysteine level is also a risk factor for AD pathology and is narrowly associated with metabolic diseases and non-alcoholic fatty liver disease. The existence of a homocysteine/ceramides signaling pathway suggests that homocysteine toxicity could be partly mediated by intracellular ceramide accumulation due to stimulation of ceramide synthase. In this article, we briefly examined the role of homocysteine and ceramide metabolism linking metabolic diseases and non-alcoholic fatty liver disease to AD. We therefore analyzed the expression of mainly enzymes implicated in ceramide and sphingolipid metabolism and demonstrated deregulation of de novo ceramide biosynthesis and S1P metabolism in liver and brain of hyperhomocysteinemic mice.

Highlights

Insulin resistance is a major public health outcome by its association with the non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, type 2 diabetes mellitus (T2DM), obesity, and Alzheimer’s disease (AD)-type neurodegeneration epidemics
Cytotoxic ceramides and related molecules generated in liver promote insulin resistance, traffic through the circulation due to injury or apoptosis caused by local liver inflammation, and because of their hydrophobic nature, can pass through the blood-brain barrier (BBB), thereby exerting toxic responses as reducing insulin signaling and increasing pro-inflammatory cytokines
Based on the results described above, we used mice heterozygous for targeted disruption of the Cbs gene (Cbs+/−) [30] and wild type (Cbs+/+) mice on the same background, fed on a standard diet supplemented with 0.5% L-methionine (SigmaAldrich, France) in drinking water to induce intermediate HHcy in Cbs+/− mice [97], and with a high-fat diabetogenic diet (HFD) [98]

Summary

INTRODUCTION

Insulin resistance is a major public health outcome by its association with the non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, type 2 diabetes mellitus (T2DM), obesity, and Alzheimer’s disease (AD)-type neurodegeneration epidemics. The increase of Cers (correlating negatively with Dyrk1A expression), the non-significant increase of Sptlc support an increased ceramide levels in liver of Cbs+/− mice on methionine and HFD mediated through specific ceramide synthases. SPTLC3 expression has been associated with NAFLD [108] and could participate to its development under the context of HHcy. We found a strong hepatic decrease of SGPL in Cbs+/− on methionine and HFD suggesting an altered catabolism of S1P. The increase of Cers, the decrease of Sphk with the non-significant increase of Sptlc and the non-significant decrease of SGPL (Sphk and SGPL correlating positively with CBS expression) support increased hypothalamic ceramide levels in HHcy mice on HFD mediated through the regulation of specific ceramide synthases. Our results suggest that local alteration of S1P metabolism could contribute to AD development associated with HHcy

CONCLUSION

Findings

ETHICS STATEMENT