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

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.

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

“…Increased tCho relative to tCr has been attributed to the cerebral infarctions, inflammation and multiple sclerosis [ 51 , 55 ]. It was recently shown that tCho was associated with the membrane turnover, which was directly related to Hcy removal [ 54 ], and a link between hHcy and ceramide metabolism was revealed in the AD-type neurodegeneration [ 52 , 56 ]. In our experiments, we did not find significant changes, neither in the levels of tCho nor the tCr, at any reperfusion time.…”

Effect of Methionine Diet on Metabolic and Histopathological Changes of Rat Hippocampus

“…Additionally, tCho is typically elevated during myelin sheet degradation [17,25] and an increase in tCho relative to tNAA and tCr was correlated with cerebral infarctions, ongoing gliosis, and ischemic and re/de-myelinization processes [19,25]. It was recently shown that tCho was associated with membrane turnover that was directly related to Hcy removal [24], and a link was revealed between hHcy and ceramide metabolism in AD-type neurodegeneration [17,25,26]. In our experiments, we did not find significant changes in the levels of tCho and tCr in the hippocampus, but the rise in its ratio suggests for the proposed process of hippocampal re/de-remyelination, neuroglial dyshomeostasis, and cell membrane turnover in MDG conditions.…”

Exploring Sphingolipid Implications in Neurodegeneration

“…Relevantly, De Wit et al (117) demonstrated that the in frontotemporal lobar dementia ceramide production in reactive astrocytes is independent of enhanced levels of aSMase but is due to an increase in the expression of CerS. It was observed also in AD (118). In this context it is very important to investigate changes in the SphL profile in the brain of animals with NDDinduced, and in CFS and blood of NDD patients during the course of this disease and its treatment.…”