Lipid Profiling of Alzheimer’s Disease Brain Highlights Enrichment in Glycerol(phospho)lipid, and Sphingolipid Metabolism

Abstract

Alzheimer’s disease (AD) is reported to be closely linked with abnormal lipid metabolism. To gain a more comprehensive understanding of what causes AD and its subsequent development, we profiled the lipidome of postmortem (PM) human brains (neocortex) of people with a range of AD pathology (Braak 0–6). Using high-resolution mass spectrometry, we employed a semi-targeted, fully quantitative lipidomics profiling method (Lipidyzer) to compare the biochemical profiles of brain tissues from persons with mild AD (n = 15) and severe AD (AD; n = 16), and compared them with age-matched, cognitively normal controls (n = 16). Univariate analysis revealed that the concentrations of 420 lipid metabolites significantly (p < 0.05; q < 0.05) differed between AD and controls. A total of 49 lipid metabolites differed between mild AD and controls, and 439 differed between severe AD and mild AD. Interestingly, 13 different subclasses of lipids were significantly perturbed, including neutral lipids, glycerolipids, glycerophospholipids, and sphingolipids. Diacylglycerol (DAG) (14:0/14:0), triacylglycerol (TAG) (58:10/FA20:5), and TAG (48:4/FA18:3) were the most notably altered lipids when AD and control brains were compared (p < 0.05). When we compare mild AD and control brains, phosphatidylethanolamine (PE) (p-18:0/18:1), phosphatidylserine (PS) (18:1/18:2), and PS (14:0/22:6) differed the most (p < 0.05). PE (p-18:0/18:1), DAG (14:0/14:0), and PS (18:1/20:4) were identified as the most significantly perturbed lipids when AD and mild AD brains were compared (p < 0.05). Our analysis provides the most extensive lipid profiling yet undertaken in AD brain tissue and reveals the cumulative perturbation of several lipid pathways with progressive disease pathology. Lipidomics has considerable potential for studying AD etiology and identifying early diagnostic biomarkers.

Phosphatidylserine, inflammation, and central nervous system diseases

“…Among these hypotheses, abnormal lipid metabolism in the cell membrane is considered as one of the mechanisms of AD. The alteration of PS and other phospholipids changes the viscosity of cell membrane and hinders many biological processes, such as enzyme activity, signal transduction efficiency, and membrane carrier ( Akyol et al, 2021 ). It is controversary about the alternation of PS in brain tissues of AD patients.…”

“…It is controversary about the alternation of PS in brain tissues of AD patients. Some studies have demonstrated PS is reduced in brains of AD patients ( Corrigan et al, 1998 ; Pettegrew et al, 2001 ; Oma et al, 2012 ; Sabogal-Guaqueta et al, 2020 ; Akyol et al, 2021 ). Meanwhile, others studies also found PS is increased or unchanged in brains of AD patients ( Wells et al, 1995 ; Lampl et al, 2006 ; Martin et al, 2010 ; Kim W. S. et al, 2018 ).…”

Combined with UPLC-Triple-TOF/MS-based plasma lipidomics and molecular pharmacology reveals the mechanisms of schisandrin against Alzheimer’s disease

“…A close relationship between TGs and cognitive impairment has been demonstrated in animal studies, which suggest that lowering triglycerides can reverse cognitive impairment and enhance oxidative stress in the brain [ 8 ]. In addition, other studies have found elevated serum DGs levels in AD patients [ 2 ]. As previously reported [ 24 ], phospholipids such as PC, PI, PE, LysoPC and LysoPE were also found to be low in AD rats in our study.…”

Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer’s Disease and Other Neurodegenerative Diseases

“…In this regard, genetic alterations in SL metabolism have been observed in brain tissue, cerebrospinal fluid (CSF), and the blood of patients with neurodegeneration [ 24 , 25 , 26 , 27 ]. Moreover, SLs have been associated with different pathological processes such as neuroinflammation and amyloid plaque formation, and thus are being proposed as promising biomarkers [ 28 , 29 , 30 ].…”