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Review
. 2023 Jan 28;12(2):293.
doi: 10.3390/antiox12020293.

Ether Lipid-Mediated Antioxidant Defense in Alzheimer's Disease

Mariona Jové  1 , Natàlia Mota-Martorell  1 , Èlia Obis  1 , Joaquim Sol  1   2 , Meritxell Martín-Garí  1 , Isidre Ferrer  3   4   5 , Manuel Portero-Otin  1 , Reinald Pamplona  1
Affiliations
Review

Ether Lipid-Mediated Antioxidant Defense in Alzheimer's Disease

Mariona Jové et al. Antioxidants (Basel). .

Abstract

One of the richest tissues in lipid content and diversity of the human body is the brain. The human brain is constitutively highly vulnerable to oxidative stress. This oxidative stress is a determinant in brain aging, as well as in the onset and progression of sporadic (late-onset) Alzheimer's disease (sAD). Glycerophospholipids are the main lipid category widely distributed in neural cell membranes, with a very significant presence for the ether lipid subclass. Ether lipids have played a key role in the evolution of the human brain compositional specificity and functionality. Ether lipids determine the neural membrane structural and functional properties, membrane trafficking, cell signaling and antioxidant defense mechanisms. Here, we explore the idea that ether lipids actively participate in the pathogenesis of sAD. Firstly, we evaluate the quantitative relevance of ether lipids in the human brain composition, as well as their role in the human brain evolution. Then, we analyze the implications of ether lipids in neural cell physiology, highlighting their inherent antioxidant properties. Finally, we discuss changes in ether lipid content associated with sAD and their physiopathological implications, and propose a mechanism that, as a vicious cycle, explains the potential significance of ether lipids in sAD.

Keywords: antioxidants; human brain; lipid oxidation; lipidomics; neurodegeneration; plasmalogens.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Glycerophospholipid distribution in the human prefrontal cortex (A), entorhinal cortex (B), and cerebellum (C) from healthy adult individuals. Lipidomic analysis was performed in a LC-MS/MS platform. Data obtained from reference [18].
Figure 2
Figure 2
Ether lipid metabolism. The ether lipid biosynthesis process initiates in peroxisomes and is subsequently completed in the endoplasmic reticulum. Briefly, the early steps of ether lipid biosynthesis in the peroxisomes are based on substrates derived from fatty acid metabolism (AcylCoA) and glycolysis (DHAP), and the rate-limiting step is the provision of FAOH. The completion of GP biosynthesis occurs in the endoplasmic reticulum using DAG and Alkyl-PA as precursor molecules. The catabolism of ether lipids proceeds by their lyso-forms for alkyl lipids, and is catalyzed by AGMO, and by (lyso)plasmalogenases in the case of alkenyl lipids. Abbreviations: AAG, alkyl-acylglycerol; AGMO, alkylglycerol monooxygenase; AGPS, alkylglycerone phosphate synthase; DAG, diacylglycerol; DHAP, dihydroxyacetone phosphate; FAOH, fatty alcohol, FAR 1 and FAR2, fatty acyl-CoA reductase; FAS, fatty acid synthase; G3P, glycerol 3-phosphate; G3PDH, glycerol 3-phosphate dehydrogenase; GNPAT, glyceronephosphate O-acyltransferase; GP, glycerophospholipid; LPA, lysophosphatidic acid; PEDS1, plasmanylethanolamine desaturase. For additional details see references [19,20].
Figure 3
Figure 3
Mechanistic pathway for the potential role of ether lipids in the pathogenesis of sporadic Alzheimer’s disease. For an explanation, see main text.
See this image and copyright information in PMC

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