Augmented frontal cortex diacylglycerol levels in Parkinson's disease and Lewy Body Disease

Abstract

Background: Research from our laboratory, and that of other investigators, has demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of subjects with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). We have extended these observations to investigate the frontal cortex of subjects with Parkinson's disease (PD) and Lewy Body Disease (LBD), with and without coexisting pathologic features of AD.

Methods/principal findings: Utilizing a high-resolution mass spectrometry analytical platform, we clearly demonstrate that DAG levels are significantly increased in the frontal cortex of subjects with PD, LBD with intermediate neocortical AD neuropathology, and in LBD with established neocortical AD neuropathology. In the case of the PD cohort, increases in cortical DAG levels were detected in cases with no neocortical pathology but were greater in subjects with neocortical pathology. These data suggest that DAG changes occur early in the disease processes and are amplified as cortical dysfunction becomes more established.

Conclusions: These findings suggest that altered DAG synthesis/metabolism is a common feature of neurodegenerative diseases, characterized by proteinopathy, that ultimately result in cognitive deficits. With regard to the mechanism responsible for these biochemical alterations, selective decrements in cortical levels of phosphatidylcholines in LBD and PD suggest that augmented degradation and/or decreased synthesis of these structural glycerophospholipids may contribute to increases in the pool size of free DAGs. The observed augmentation of DAG levels may be phospholipase-driven since neuroinflammation is a consistent feature of all disease cohorts. If this conclusion can be validated it would support utilizing DAG levels as a biomarker of the early disease process and the investigation of early intervention with anti-inflammatory agents.

Fig 1. Frontal cortex levels of diacylglycerols (DAG) and lysophosphatidic acid 16:0 (LPA) in control, Lewy body disease with intermediate Alzheimer’s disease (LBD-I-AD), Lewy body disease with Alzheimer’s disease (LBD-AD), and Parkinson’s disease (PD) tissues.

R = ratio of the peak area of the endogenous lipid to the peak area of the internal standard (mean ±SEM). Analysis of PD subgroups demonstrated that DAGs were augmented in the cortex of PD subjects with no neocortical pathology (PD-1, N = 5), subjects with sparse neocortical neuritic plaques (PD-2, N = 5), and subjects with moderate to frequent neocortical neuritic plaques (PD-3, N = 5). *, p < 0.01 vs. controls; #, p < 0.05 for PD-2 vs. PD3.

Fig 2. Frontal cortex levels of plasmalogens in control, Lewy body disease with intermediate Alzheimer’s disease (LBD-I-AD), Lewy body disease with Alzheimer’s disease (LBD-AD), and Parkinson’s disease (PD) tissues.

PlsC, choline plasmalogens; PlsE, ethanolamine plasmalogen. R = ratio of the peak area of the endogenous plasmalogen to the peak area of the internal standard (mean ±SEM). *, p < 0.05 vs controls.

Fig 3. Frontal cortex levels of sphingolipids (SM, sphingomyelin; Sul, sulfatide, Cer, ceramide; G-Cer, galactosyceramide; L-Cer, lactosylceramide) in control, Lewy body disease with intermediate Alzheimer’s disease (LBD-I-AD), Lewy body disease with Alzheimer’s disease (LBD-AD), and Parkinson’s disease (PD) tissues.

R = ratio of the peak area of the endogenous sphingolipid to the peak area of the internal standard (mean ±SEM). *, p < 0.05. vs controls.

Fig 4. Decreased frontal cortex levels of 20:5-containing phosphatidylcholines (PtdC) in Lewy body disease with intermediate Alzheimer’s disease (LBD-I-AD), Lewy body disease with Alzheimer’s disease (LBD-AD), and Parkinson’s disease (PD) tissues.

R = ratio of the peak area of the endogenous PtdC to the peak area of the internal standard (mean ±SEM). *, p < 0.01; #, p < 0.05 vs controls.

Fig 5. Frontal cortex levels of phosphatidylserines (PtdS), phosphatidylglycerol 32:0 (PtdG), and lysophosphatidylglycerol 16:0 (LPG) in control, Lewy body disease with intermediate Alzheimer’s disease (LBD-I-AD), Lewy body disease with Alzheimer’s disease (LBD-AD), and Parkinson’s disease (PD) tissues.

R = ratio of the peak area of the endogenous lipid to the peak area of the internal standard (mean ±SEM). *, p < 0.01 vs controls.

Fig 6. Abbreviated schematic presentation of DAG metabolism.

LPA, lysophosphatidic acid; PC, phosphatidylcholine; PG, phosphatidylglycerol; PS, phosphatidylserine; PLC, phospholipase C; PLD, phospholipase D; SMS, sphingomyelin synthase; DGK, diacylglycerol kinase. Red indicates lowered levels and blue indicates increased levels observed in our study.

Fig 7. Abbreviated schematic presentation of sphingolipid metabolism.

Gal, galactosyl; Glu, glucosyl; Lac, lactosyl; S-1-P, sphingosine-1-phosphate. Red indicates lowered levels and blue indicates increased levels observed in our study.