Effects of Sex, Age, and Apolipoprotein E Genotype on Brain Ceramides and Sphingosine-1-Phosphate in Alzheimer’s Disease and Control Mice

Hoedt, Sandra den; Crivelli, Simone M.; Leijten, Frank; Losen, Mario; Stevens, Jo; Mané-Damas, Marina; Vries, Helga E. de; Walter, Jochen; Mirzaian, Mina; Sijbrands, Eric; Aerts, Johannes M. F. G.; Verhoeven, Adrie J.M.; Martínez‐Martínez, Pilar; Mulder, Monique

doi:10.3389/fnagi.2021.765252

Cited by 14 publications

(11 citation statements)

References 91 publications

(117 reference statements)

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“…Furthermore, alterations in sphingosine‐1‐P levels were described in brain tissue and serum of individuals suffering from age‐related neurodegenerative and cardiovascular diseases (Velazquez et al, 2021 ). Our results (validated in independent cohorts) indicated that the levels of this sphingolipid decreased with age in both women and men, although some papers indicated sex‐specific regulation in both plasma (Guo et al, 2014 ) and brain tissue (den Hoedt et al, 2021 ) in human beings and animal models. The negative correlation of sphingosine‐1‐P levels with aging could explain, at least partially, the physiological cognitive decline characteristic of the aging process.…”

Section: Discussionsupporting

confidence: 60%

Plasma acylcarnitines and gut‐derived aromatic amino acids as sex‐specific hub metabolites of the human aging metabolome

et al. 2023

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Aging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of “omic” techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high‐throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30–100 years old; 2: n = 68, 70% females, 19–107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial β‐oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut‐derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age‐related diseases.

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Section: Discussionsupporting

confidence: 60%

Plasma acylcarnitines and gut‐derived aromatic amino acids as sex‐specific hub metabolites of the human aging metabolome

et al. 2023

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“…In mice, APP SL females (characterized by the presence of Aβ plaques in the frontal cortex) presented decreased levels of ceramides containing saturated fatty acids and increased levels of ceramides containing unsaturated fatty acids compared to APP SL males (Barrier et al, 2010). Opposite results were found in the AD mouse model based on the APOE4 expression (den Hoedt et al, 2021). Likewise, sex influenced the hippocampal sphingolipid profile in healthy humans carrying the APOE4 genotype (>65 years old): total ceramides, SM, and sulfatides were increased in males but not in females (Couttas et al, 2018).…”

Section: Brain Lipid Changes: Effect Of Sex On Neurodegenerative Dise...mentioning

confidence: 91%

“…Studies using different experimental models demonstrated that the sphingolipid profile in the cortex showed a sex‐specific pattern (Barrier et al, 2010; den Hoedt et al, 2021). In mice, APP SL females (characterized by the presence of Aβ plaques in the frontal cortex) presented decreased levels of ceramides containing saturated fatty acids and increased levels of ceramides containing unsaturated fatty acids compared to APP SL males (Barrier et al, 2010).…”

Section: Brain Lipid Changes: Effect Of Sex On Neurodegenerative Dise...mentioning

confidence: 99%

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Fundamental neurochemistry review: Old brain stories ‐ Influence of age and sex on the neurodegeneration‐associated lipid changes

Cuenca‐Bermejo

Prinetti

Kublickiene

et al. 2023

Journal of Neurochemistry

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Brain aging is a naturally occurring process resulting in the decline of cognitive functions and increased vulnerability to develop age-associated disorders. Fluctuation in lipid species is crucial for normal brain development and function. However, impaired lipid metabolism and changes in lipid composition in the brain have been increasingly recognized to play a crucial role in physiological aging, as well as in several neurodegenerative diseases. In the last decades, the role of sexual dimorphism in the vulnerability to develop age-related neurodegeneration has increased. However, further studies are warranted for detailed assessment of how age, sex, and additional non-biological factors may influence the lipid changes in brains. The aim of this work is to address the presence of sex differences in the brain lipid changes that occur along aging, and in the two most common age-related neurodegenerative disorders (Alzheimer's and Parkinson's diseases). We included the studies that assessed lipid-related alterations in the brain of both humans and experimental models. Additionally, we explored the influence of sex on lipid-lowering therapies. We conclude that sex exerts a notable effect on lipid modifications occurring with age and neurodegeneration, and

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“…Sphingolipid analysis was performed according to Mielke et al [ 44 ] and described previously [ 45 ]. Of the lipid extracts from CSF, plasma and DGUC fraction, 5, 5 and 10μl were injected by an autosampler (Shimadzu, Kyoto, Japan) into a Shimadzu HPLC system (Shimadzu) equipped with a Kinetex C8 column (50×2.1 mm, 2.6μm, Phenomenex, Maarssen, the Netherlands) at 30°C.…”

Section: Methodsmentioning

confidence: 99%

Sphingolipids in Cerebrospinal Fluid and Plasma Lipoproteins of APOE4 Homozygotes and Non-APOE4 Carriers with Mild Cognitive Impairment versus Subjective Cognitive Decline

Hoedt

Dorst-Lagerwerf

Vries

et al. 2023

Journal of Alzheimer's Disease Reports

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Background: Alzheimer’s disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD. Objective: To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD. Methods: Patients homozygous for APOE4 and non-APOE4 carriers with mild cognitive impairment (MCI; n = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ42 levels in CSF were determined by immunoassay. Results: APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p = 0.042), SM(d18:1/18:0) (p = 0.026), and Aβ 42 (p < 0.001) in CSF than non-APOE4 carriers. CSF-Aβ 42 correlated with Cer(d18:1/18:0), SM(d18:1/18:0), and SM(d18:1/18:1) levels in APOE4 homozygotes (r > 0.49; p < 0.032) and with Cer(d18:1/24:1) in non-APOE4 carriers (r = 0.50; p = 0.025). CSF-Aβ 42 correlated positively with Cer(d18:1/24:0) in MCI (p = 0.028), but negatively in SCD patients (p = 0.019). Levels of Cer(d18:1/22:0) and long-chain SMs were inversely correlated with Mini-Mental State Examination score among MCI patients, independent of APOE4 genotype (r< –0.47; p < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the APOE genotype or the cognitive state. In HDL, ratios of Cer(d18:1/18:0) and Cer(d18:1/22:0) to cholesterol were higher in APOE4 homozygotes than in non-APOE4 carriers (p = 0.048 and 0.047, respectively). Conclusion: The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism.

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Effects of Sex, Age, and Apolipoprotein E Genotype on Brain Ceramides and Sphingosine-1-Phosphate in Alzheimer’s Disease and Control Mice

Cited by 14 publications

References 91 publications

Plasma acylcarnitines and gut‐derived aromatic amino acids as sex‐specific hub metabolites of the human aging metabolome

Plasma acylcarnitines and gut‐derived aromatic amino acids as sex‐specific hub metabolites of the human aging metabolome

Fundamental neurochemistry review: Old brain stories ‐ Influence of age and sex on the neurodegeneration‐associated lipid changes

Sphingolipids in Cerebrospinal Fluid and Plasma Lipoproteins of APOE4 Homozygotes and Non-APOE4 Carriers with Mild Cognitive Impairment versus Subjective Cognitive Decline

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