Age-Dependent Changes to Sphingolipid Balance in the Human Hippocampus are Gender-Specific and May Sensitize to Neurodegeneration

Age-Dependent Changes to Sphingolipid Balance in the Human Hippocampus are Gender-Specific and May Sensitize to Neurodegeneration.

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Journal of Alzheimer's Disease
Volume: 63
Number: 2
Page Range: pp. 503-514
Date: 2018
Divisions: Lipid Metabolism and Neurochemistry
Depositing User: General Admin
Identification Number: 10.3233/JAD-171054
ISSN: 13872877
Date Deposited: 04 Jan 2021 23:32

The greatest risk factor for developing Alzheimer’s disease (AD) is aging. The major genetic risk factor for AD is the ɛ4 allele of the APOE gene, encoding the brain’s major lipid transport protein, apolipoprotein E (ApoE). The research community is yet to decipher why the ApoE4 variant pre-disposes to AD, and how aging causes the disease. Studies have shown deregulated levels of sphingolipids, including decreased levels of the neuroprotective signaling lipid sphingosine 1-phosphate (S1P), and increased ceramide content, in brain tissue and serum of people with pre-clinical or very early AD. In this study we investigated whether sphingolipid levels are affected as a function of age or APOE genotype, in the hippocampus of neurologically normal subjects over the age of 65. Lipids were quantified in 80 postmortem tissue samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Sphingolipid levels were not significantly affected by the presence of one ɛ4 or ɛ2 allele. However, ceramide, sphingomyelin, and sulfatide content was very significantly correlated with age in the hippocampus of males. On the other hand, S1P, normalized to its non-phosphorylated precursor sphingosine, was inversely correlated with age in females. Our results therefore establish gender-specific differences in sphingolipid metabolism in the aging human brain. Ceramide is a pro-apoptotic lipid, and heavily implicated as a driver of insulin resistance in metabolic tissues. S1P is a neuroprotective lipid that supports glutamatergic neurotransmission. Increasing ceramide and decreasing S1P levels may contribute significantly to a pro-neurodegenerative phenotype in the aging brain.

Couttas, Timothy A.
Kain, Nupur
Tran, Collin
Chatterton, Zac
Kwok, John B.
Don, Anthony S.
Mielke, Michelle
Last Modified: 04 Jan 2021 23:32

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