Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels

Sandra den Hoedt; Carola I. F. Janssen; Giuseppe Astarita; Daniele Piomelli; Frank P. J. Leijten; Simone M. Crivelli; Adrie J. M. Verhoeven; Helga E. de Vries; Jochen Walter; Pilar Martinez-Martinez; Eric J. G. Sijbrands; Amanda J. Kiliaan; Monique T. Mulder

doi:10.3233/JAD-160739

Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels

Sandra den Hoedt, Carola I. F. Janssen, Giuseppe Astarita, Daniele Piomelli, Frank P. J. Leijten, Simone M. Crivelli, Adrie J. M. Verhoeven, Helga E. de Vries, Jochen Walter, Pilar Martinez-Martinez, Eric J. G. Sijbrands, Amanda J. Kiliaan, Monique T. Mulder^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the epsilon 4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD.

Objective: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet.

Methods: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR.

Results: Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice.

Conclusion: hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.

Original language	English
Pages (from-to)	769-781
Number of pages	13
Journal	Journal of Alzheimer's Disease
Volume	60
Issue number	3
DOIs	https://doi.org/10.3233/JAD-160739
Publication status	Published - 3 Oct 2017

Keywords

Alzheimer's disease
apolipoprotein E4
ceramides
fatty acids
high fat diet
sphingolipids
MOUSE APOLIPOPROTEIN-E
HIGH-CHOLESTEROL DIET
AMYLOID-BETA PEPTIDE
BLOOD-BRAIN-BARRIER
KNOCK-IN MICE
ALZHEIMERS-DISEASE
BINDING PROTEIN
SPHINGOLIPID METABOLISM
NEURODEGENERATIVE DISEASES
DENSITY-LIPOPROTEIN

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den Hoedt, S., Janssen, C. I. F., Astarita, G., Piomelli, D., Leijten, F. P. J., Crivelli, S. M., Verhoeven, A. J. M., de Vries, H. E., Walter, J., Martinez-Martinez, P., Sijbrands, E. J. G., Kiliaan, A. J., & Mulder, M. T. (2017). Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels. Journal of Alzheimer's Disease, 60(3), 769-781. https://doi.org/10.3233/JAD-160739

@article{a915d99070694c38ac63fc347f5eaca6,

title = "Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels",

abstract = "Background: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the epsilon 4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD.Objective: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet.Methods: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR.Results: Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice.Conclusion: hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.",

keywords = "Alzheimer's disease, apolipoprotein E4, ceramides, fatty acids, high fat diet, sphingolipids, MOUSE APOLIPOPROTEIN-E, HIGH-CHOLESTEROL DIET, AMYLOID-BETA PEPTIDE, BLOOD-BRAIN-BARRIER, KNOCK-IN MICE, ALZHEIMERS-DISEASE, BINDING PROTEIN, SPHINGOLIPID METABOLISM, NEURODEGENERATIVE DISEASES, DENSITY-LIPOPROTEIN",

author = "{den Hoedt}, Sandra and Janssen, {Carola I. F.} and Giuseppe Astarita and Daniele Piomelli and Leijten, {Frank P. J.} and Crivelli, {Simone M.} and Verhoeven, {Adrie J. M.} and {de Vries}, {Helga E.} and Jochen Walter and Pilar Martinez-Martinez and Sijbrands, {Eric J. G.} and Kiliaan, {Amanda J.} and Mulder, {Monique T.}",

year = "2017",

month = oct,

day = "3",

doi = "10.3233/JAD-160739",

language = "English",

volume = "60",

pages = "769--781",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "IOS Press",

number = "3",

}

den Hoedt, S, Janssen, CIF, Astarita, G, Piomelli, D, Leijten, FPJ, Crivelli, SM, Verhoeven, AJM, de Vries, HE, Walter, J, Martinez-Martinez, P, Sijbrands, EJG, Kiliaan, AJ & Mulder, MT 2017, 'Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels', Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 769-781. https://doi.org/10.3233/JAD-160739

TY - JOUR

T1 - Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels

AU - den Hoedt, Sandra

AU - Janssen, Carola I. F.

AU - Astarita, Giuseppe

AU - Piomelli, Daniele

AU - Leijten, Frank P. J.

AU - Crivelli, Simone M.

AU - Verhoeven, Adrie J. M.

AU - de Vries, Helga E.

AU - Walter, Jochen

AU - Martinez-Martinez, Pilar

AU - Sijbrands, Eric J. G.

AU - Kiliaan, Amanda J.

AU - Mulder, Monique T.

PY - 2017/10/3

Y1 - 2017/10/3

N2 - Background: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the epsilon 4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD.Objective: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet.Methods: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR.Results: Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice.Conclusion: hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.

AB - Background: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the epsilon 4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD.Objective: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet.Methods: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR.Results: Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice.Conclusion: hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.

KW - Alzheimer's disease

KW - apolipoprotein E4

KW - ceramides

KW - fatty acids

KW - high fat diet

KW - sphingolipids

KW - MOUSE APOLIPOPROTEIN-E

KW - HIGH-CHOLESTEROL DIET

KW - AMYLOID-BETA PEPTIDE

KW - BLOOD-BRAIN-BARRIER

KW - KNOCK-IN MICE

KW - ALZHEIMERS-DISEASE

KW - BINDING PROTEIN

KW - SPHINGOLIPID METABOLISM

KW - NEURODEGENERATIVE DISEASES

KW - DENSITY-LIPOPROTEIN

U2 - 10.3233/JAD-160739

DO - 10.3233/JAD-160739

M3 - Article

C2 - 28035926

SN - 1387-2877

VL - 60

SP - 769

EP - 781

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

IS - 3

ER -

Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels

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