Cigarette Smoke-Induced Alterations in Frontal White Matter Lipid Profiles Demonstrated by MALDI-Imaging Mass Spectrometry: Relevance to Alzheimer’s Disease

Abstract

Background Meta-analysis has shown that smokers have significantly increased risks for Alzheimer’s disease (AD), and neuroimaging studies showed that smoking alters white matter (WM) structural integrity. Objective Herein, we characterize the effects of cigarette smoke (CS) exposures and withdrawal on WM myelin lipid composition using matrix assisted laser desorption and ionization-imaging mass spectrometry (MALDI-IMS). Methods Young adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). Frontal lobe WM was examined for indices of lipid and protein oxidation and lipid profile alterations by MALDI-IMS. Lipid ions were identified by MS/MS with the LIPID MAPS prediction tools database. Inter-group comparisons were made using principal component analysis and R-generated heatmap. Results CS increased lipid and protein adducts such that higher levels were present in CS8 compared with CS4 samples. CS8 + R reversed CS8 effects and normalized the levels of oxidative stress. MALDI-IMS demonstrated striking CS-associated alterations in WM lipid profiles characterized by either reductions or increases in phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine) and sphingolipids (sulfatides), and partial reversal of CS’s inhibitory effects with recovery. The heatmap hierarchical dendrogram and PCA distinguished CS exposure, duration, and withdrawal effects on WM lipid profiles. Conclusion CS-mediated WM degeneration is associated with lipid peroxidation, protein oxidative injury, and alterations in myelin lipid composition, including shifts in phospholipids and sphingolipids needed for membrane integrity, plasticity, and intracellular signaling. Future goals are to delineate WM abnormalities in AD using MALDI-IMS, and couple the findings with MRI-mass spectroscopy to improve in vivo diagnostics and early detection of brain biochemical responses to treatment.

Progressive white matter atrophy with altered lipid profiles is partially reversed by short-term abstinence in an experimental model of alcohol-related neurodegeneration

“…The proportions of sphingolipids (25%) and phospholipids (53%) and the spectra of sphingolipids (sulfatides, sphingomyelins, and lactosylceramides) and phospholipids (phosphatidylserines, phosphatidylinositols, phosphatidylethanolamines, plasmalogens, and phosphatidylglycerols) identified in WM are consistent with previous reports in which MALDI-TOF IMS was performed in the negative ionization mode (Nunez et al, 2016; O'Brien & Sampson, 1965; Yalcin et al, 2015). In contrast, other abundant lipids in myelin, including cholesterol, phosphatidylcholine, and sphingomyelin, which form protonated ([M+H] + ), sodiated ([M+Na] + ), or potassiated ([M+K] + ) adducts, were not detected because they are preferentially accessible via positive ionization mode mass spectrometry (Berry et al, 2011; Löhmann, Schachmann, Dandekar, Villmann, & Becker, 2010).…”

“…Barplots were generated in R using the ggplot2 module to visualize the mean percent changes in lipid ion expression. Heatmap hierarchical clustering analysis and data barplots were generated as reported (Nunez et al, 2016). Principal component analysis (PCA) generated by ClinProTools was used to compare lipid ion expression patterns among groups.…”

Alzheimer's Disease and NQO1: Is there a Link?

“…Consistent with the inhibition of Nrf2-dependent gene expression, chronic cigarette smoking has also been reported as a significant risk factor for inducing AD pathology in preclinical and clinical studies [132,133]. This observation is supported by reports that suggest smoking-associated cerebral-oxidative stress is potentially contributing to AD pathology [132,134].…”

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“…Infrared spectroscopy is widely used in amyloid research [25][26][27][28] focusing mostly on the absorption of the amide I vibrations. These vibrations consist mainly of the stretching vibration of the carbonyl groups of the peptide backbone.…”