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. 2020 Jul 1;11(4):760-772.
doi: 10.1093/advances/nmaa024.

Perspective: The Potential Role of Circulating Lysophosphatidylcholine in Neuroprotection against Alzheimer Disease

Richard D Semba  1
Affiliations

Perspective: The Potential Role of Circulating Lysophosphatidylcholine in Neuroprotection against Alzheimer Disease

Richard D Semba. Adv Nutr. .

Abstract

Alzheimer disease (AD), the most common cause of dementia, is a progressive disorder involving cognitive impairment, loss of learning and memory, and neurodegeneration affecting wide areas of the cerebral cortex and hippocampus. AD is characterized by altered lipid metabolism in the brain. Lower concentrations of long-chain PUFAs have been described in the frontal cortex, entorhinal cortex, and hippocampus in the brain in AD. The brain can synthesize only a few fatty acids; thus, most fatty acids must enter the brain from the blood. Recent studies show that PUFAs such as DHA (22:6) are transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC) via a specific LPC receptor at the BBB known as the sodium-dependent LPC symporter 1 (MFSD2A). Higher dietary PUFA intake is associated with decreased risk of cognitive decline and dementia in observational studies; however, PUFA supplementation, with fatty acids esterified in triacylglycerols did not prevent cognitive decline in clinical trials. Recent studies show that LPC is the preferred carrier of PUFAs across the BBB into the brain. An insufficient pool of circulating LPC containing long-chain fatty acids could potentially limit the supply of long-chain fatty acids to the brain, including PUFAs such as DHA, and play a role in the pathobiology of AD. Whether adults with low serum LPC concentrations are at greater risk of developing cognitive decline and AD remains a major gap in knowledge. Preventing and treating cognitive decline and the development of AD remain a major challenge. The LPC pathway is a promising area for future investigators to identify modifiable risk factors for AD.

Keywords: Alzheimer disease; blood–brain barrier; cognition; dementia; docosahexaenoic acid; lysophosphatidylcholine; polyunsaturated fatty acid.

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Figures

FIGURE 1
FIGURE 1
Examples of LPC species, showing fatty acid chains in the sn-1 position. LPC, lysophosphatidylcholine.
FIGURE 2
FIGURE 2
Metabolic pathway of LPC from the diet to the brain, with an emphasis on LPC-DHA because of the importance of DHA in the brain (17). Dietary sources of DHA are seafood and fish, which contain DHA esterified in LPC (31–33) or in PC. PCs in the diet generally have saturated fatty acids esterified in the sn-1 position and PUFAs such as DHA in the sn-2 position (39). During digestion, PLA2 cleaves fatty acids from the sn-2 position of PC in the gut, generating LPC with fatty acids at the sn-1 position. LPC-DHA is absorbed by diffusion across enterocytes, circulates in the blood, and is transported by MFSD2A across the blood–brain barrier. MFSD2A transports LPCs with fatty acids at either sn-1 or sn-2 with equal efficiency into the brain (49). Through the Lands’ cycle, LPC-DHA is remodeled in brain membranes as PC via LPCAT or converted back to LPC via PLA2. LPC-DHA can be converted to LPA by ATX, with DHA becoming incorporated in cardiolipin in mitochondrial membranes. LPA can bind to specific G protein–coupled receptors. Some LPC-DHA is generated by PLA1 on PCs in the liver, but the conversion is not efficient (39). ATX, autotaxin; CoA-SH, coenzyme A; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; LPCAT, LPC acyltransferase; MFSD2A, sodium-dependent LPC symporter 1; PC, phosphatidylcholine; PLA1, phospholipase A1; PLA2, phospholipase A2.
FIGURE 3
FIGURE 3
Distribution of 21 serum LPC species as measured by LC–tandem MS (53) in 100 women, aged 71–89 y, in the Women's Health and Aging Study II, a population-based study of the two-thirds least-disabled women living in the community (RD Semba, P Zhang, LP Fried, previously unpublished data, 2019). LPC, lysophosphatidylcholine.
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