The isoform-specific pathological effects of ApoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol

Zehavit Kariv-Inbal, Shiri Yacobson, R. Berkecz, Maria Peter, T. Janáky, Dieter Lütjohann, Laus M. Broersen, Tobias Hartmann, Daniel M. Michaelson

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD). Epidemiological studies revealed that consumption of docosahexaenoic acid (DHA: 22:6 (ω3)), a major brain polyunsaturated fatty acid, is protective for AD and that elevated cholesterol levels are an AD risk factor. We presently investigated the extent to which the pathological effects of apoE4 in vivo can be prevented by consuming fish oil (DHA) or can be modified by cholesterol. Accordingly, apoE3- and apoE4-targeted replacement mice were subjected, following weaning, to a fish oil diet enriched in DHA and to a cholesterol-containing diet under regular and enriched environments. Cholesterol metabolism in the hippocampus and the corresponding phospholipid and fatty acid levels were affected by fish oil (DHA) and cholesterol diets and by environmental stimulation. Importantly, cholesterol metabolism and the fatty acid levels were not affected by apoE4. The phospholipid levels were, however, affected by apoE4. This effect was most pronounced in the cholesterol-fed mice and was abolished by the fish oil (DHA) diet. ApoE4 elevated hippocampal intraneuronal amyloid-β levels under regular conditions and lowered them following environmental stimulation, relative to those of the apoE3 mice. ApoE4 also elevated the levels of the presynaptic transporters Vglut and Vgat, and decreased behavioral performance in an object recognition test. Importantly, all of these apoE4 phenotypes were abolished by the fish oil (DHA) diet, whereas the cholesterol diet modified them. These findings suggest that a fish oil (DHA) diet could be used to attenuate the effects of apoE4 in AD.

Original languageEnglish
Pages (from-to)667-683
Number of pages17
JournalJournal of Alzheimer's Disease
Volume28
Issue number3
DOIs
Publication statusPublished - 2012

Fingerprint

Apolipoprotein E4
Fish Oils
Protein Isoforms
Cholesterol
Diet
Alzheimer Disease
Apolipoprotein E3
Phospholipids
Fatty Acids
Docosahexaenoic Acids
Hypercholesterolemia
Weaning
Unsaturated Fatty Acids
Amyloid
Epidemiologic Studies
Hippocampus
Phenotype

Keywords

  • Alzheimer's disease
  • amyloid-β
  • apolipoprotein E4
  • cholesterol
  • DHA
  • GABAergic
  • glutamatergic

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

Cite this

The isoform-specific pathological effects of ApoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol. / Kariv-Inbal, Zehavit; Yacobson, Shiri; Berkecz, R.; Peter, Maria; Janáky, T.; Lütjohann, Dieter; Broersen, Laus M.; Hartmann, Tobias; Michaelson, Daniel M.

In: Journal of Alzheimer's Disease, Vol. 28, No. 3, 2012, p. 667-683.

Research output: Contribution to journalArticle

Kariv-Inbal, Zehavit ; Yacobson, Shiri ; Berkecz, R. ; Peter, Maria ; Janáky, T. ; Lütjohann, Dieter ; Broersen, Laus M. ; Hartmann, Tobias ; Michaelson, Daniel M. / The isoform-specific pathological effects of ApoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol. In: Journal of Alzheimer's Disease. 2012 ; Vol. 28, No. 3. pp. 667-683.
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abstract = "Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD). Epidemiological studies revealed that consumption of docosahexaenoic acid (DHA: 22:6 (ω3)), a major brain polyunsaturated fatty acid, is protective for AD and that elevated cholesterol levels are an AD risk factor. We presently investigated the extent to which the pathological effects of apoE4 in vivo can be prevented by consuming fish oil (DHA) or can be modified by cholesterol. Accordingly, apoE3- and apoE4-targeted replacement mice were subjected, following weaning, to a fish oil diet enriched in DHA and to a cholesterol-containing diet under regular and enriched environments. Cholesterol metabolism in the hippocampus and the corresponding phospholipid and fatty acid levels were affected by fish oil (DHA) and cholesterol diets and by environmental stimulation. Importantly, cholesterol metabolism and the fatty acid levels were not affected by apoE4. The phospholipid levels were, however, affected by apoE4. This effect was most pronounced in the cholesterol-fed mice and was abolished by the fish oil (DHA) diet. ApoE4 elevated hippocampal intraneuronal amyloid-β levels under regular conditions and lowered them following environmental stimulation, relative to those of the apoE3 mice. ApoE4 also elevated the levels of the presynaptic transporters Vglut and Vgat, and decreased behavioral performance in an object recognition test. Importantly, all of these apoE4 phenotypes were abolished by the fish oil (DHA) diet, whereas the cholesterol diet modified them. These findings suggest that a fish oil (DHA) diet could be used to attenuate the effects of apoE4 in AD.",
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AU - Yacobson, Shiri

AU - Berkecz, R.

AU - Peter, Maria

AU - Janáky, T.

AU - Lütjohann, Dieter

AU - Broersen, Laus M.

AU - Hartmann, Tobias

AU - Michaelson, Daniel M.

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AB - Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD). Epidemiological studies revealed that consumption of docosahexaenoic acid (DHA: 22:6 (ω3)), a major brain polyunsaturated fatty acid, is protective for AD and that elevated cholesterol levels are an AD risk factor. We presently investigated the extent to which the pathological effects of apoE4 in vivo can be prevented by consuming fish oil (DHA) or can be modified by cholesterol. Accordingly, apoE3- and apoE4-targeted replacement mice were subjected, following weaning, to a fish oil diet enriched in DHA and to a cholesterol-containing diet under regular and enriched environments. Cholesterol metabolism in the hippocampus and the corresponding phospholipid and fatty acid levels were affected by fish oil (DHA) and cholesterol diets and by environmental stimulation. Importantly, cholesterol metabolism and the fatty acid levels were not affected by apoE4. The phospholipid levels were, however, affected by apoE4. This effect was most pronounced in the cholesterol-fed mice and was abolished by the fish oil (DHA) diet. ApoE4 elevated hippocampal intraneuronal amyloid-β levels under regular conditions and lowered them following environmental stimulation, relative to those of the apoE3 mice. ApoE4 also elevated the levels of the presynaptic transporters Vglut and Vgat, and decreased behavioral performance in an object recognition test. Importantly, all of these apoE4 phenotypes were abolished by the fish oil (DHA) diet, whereas the cholesterol diet modified them. These findings suggest that a fish oil (DHA) diet could be used to attenuate the effects of apoE4 in AD.

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