APOE ε4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical Mild Cognitive Impairment/Alzheimer’s Disease

Abdullah, Laila; Evans, James E.; Emmerich, Tanja; Crynen, Gogce; Shackleton, Ben; Keegan, Andrew P.; Luis, Cheryl A.; Tai, Leon M.; LaDu, Mary Jo; Mullan, Michael; Crawford, Fiona; Bachmeier, Corbin

doi:10.18632/aging.101203

Cited by 44 publications

(50 citation statements)

References 67 publications

(90 reference statements)

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“…The role of brain DHA:AA ratio in the diagnosis of MCI/ AD has recently been highlighted (44), but there is little information on how it is influenced by sex, age, and APOE4 genotype. Our results showed that, in the cortex, DHA:AA ratio decreased with age, and this decrease was more pronounced in animals with an APOE4 genotype independent of sex, with the reduced level of DHA mainly responsible for the decreased ratio.…”

Section: Lower Cortical Dha Associated With Lower Pe-dhamentioning

confidence: 99%

Altered SPMs and age‐associated decrease in brain DHA inAPOE4female mice

et al. 2019

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An apolipoprotein E (APOE) 4 genotype is the most important, common genetic determinant for Alzheimer disease (AD), and female APOE4 carriers present with an increased risk compared with males. The study quantified cortical and hippocampal fatty acid and phospholipid profiles along with select eicosapentaenoic acid (EPA)‐ and docosahexaenoic acid (DHA)‐derived specialized proresolving mediators (SPMs) in 2‐, 9‐, and 18‐mo‐old APOE3 and APOE4 male and female mice. A 10% lower cortical DHA was evident in APOE4 females at 18 mo compared with 2 mo, with no significant decrease in APOE3 or APOE4 males. This decrease was associated with a reduction in DHA‐phosphatidylethanolamine. Older APOE4 females had a 15% higher oleic acid content compared with young mice. Although no sex* APOE genotype interactions were observed for SPMs expressed as a ratio of their parent compound, higher cortical 18R/S‐hydroxy‐5Z,8Z,11Z,14Z,16E‐EPA, resolvin D3, protectin D1, 10S,17S‐dihydroxy‐4Z,7Z,11E,13E,15Z,19Z‐DHA (10S,17S‐diHDHA), maresin 1, 17S‐hydroxy‐4Z,7Z,10Z,13Z,15E,19Z‐DHA, and 14S‐hydroxy‐4Z,7Z,10Z,12E,16Z,19Z‐DHA were evident in females, and lower cortical 17R‐resolvin D1, 10S,17S‐diHDHA, and 18‐HEPE in APOE4. Our findings show a strong association between age, female sex, and an APOE4 genotype, with decreased cortical DHA and a number of SPMs, which together may contribute to the development of cognitive decline and AD pathology.—Martinsen, A., Tejera, N., Vauzour, D., Harden, G., Dick, J., Shinde, S., Barden, A., Mori, T. A., Minihane, A. M. Altered SPMs and age‐associated decrease in brain DHA in APOE4 female mice. FASEB J. 33, 10315–10326 (2019). http://www.fasebj.org

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Section: Lower Cortical Dha Associated With Lower Pe-dhamentioning

confidence: 99%

Altered SPMs and age‐associated decrease in brain DHA inAPOE4female mice

et al. 2019

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“…Longitudinal profiling of E3FAD and E4FAD mice showed that blood AA-and DHA-containing PL species were altered as early as 2.5 months of age. At 6 months, AA-and DHA-containing lysophosphatidylcholine species increased in blood, but decreased in the brains of E4FAD compared with E3FAD mice (173). Previous studies have shown that lysophosphatidylcholine-DHA is a preferred DHA carrier to the brain (174), and that the major facilitator superfamily domaincontaining protein 2 (mfsd2a) transports this lipid across the blood-brain barrier (BBB) (175,176).…”

Section: Apoe Modulated Ad Symptoms Exhibited In Efad Micementioning

confidence: 99%

EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerŉs disease

Tai

Balu

Avila-Munoz

et al. 2017

Journal of Lipid Research

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Identified in 1993, is the greatest genetic risk factor for sporadic Alzheimer's disease (AD), increasing risk up to 15-fold compared with, with decreasing AD risk. However, the functional effects of on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)- genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h- rather than mouse (m)- The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid-β (Aβ) deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits. EFAD mice were designed as a temporally useful preclinical FAD-Tg-mouse model expressing the h- genotypes for identifying mechanisms underlying -modulated symptoms of AD pathology. From their first description in 2012, EFAD mice have enabled critical basic and therapeutic research. Here we review insights gleaned from the EFAD mice and summarize future directions.

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“…Lower Mfsd2a levels correlated with lower DHA and a higher ARA levels in brain membrane (Abdullah et al, 2016). Her group also showed that E4 carriers converting to mild cognitive impairment (MCI)/AD had higher ARA: DHA ratio in PC and lyso-PC compared to cognitively normal E4 carriers and E4 non-carriers (Abdullah et al, 2017). Aldullah et al also reported a similar higher ARA: DHA ratio in PC and lyso-PC in hAPOE4 mice compared to hAPOE3 mice supporting that this mice model also have an imbalance in DHA and ARA compartment packaging (Abdullah et al, 2017).…”

Section: Evidence Of Effective Prevention Strategiesmentioning

confidence: 91%

“…Her group also showed that E4 carriers converting to mild cognitive impairment (MCI)/AD had higher ARA: DHA ratio in PC and lyso-PC compared to cognitively normal E4 carriers and E4 non-carriers (Abdullah et al, 2017). Aldullah et al also reported a similar higher ARA: DHA ratio in PC and lyso-PC in hAPOE4 mice compared to hAPOE3 mice supporting that this mice model also have an imbalance in DHA and ARA compartment packaging (Abdullah et al, 2017). In ∼35 year-old humans, a positron emission tomography study with [1-11 C]-DHA reported however, that the mean global gray matter incorporation of DHA in the brain of E4 carriers was 16% higher than in non-carriers (Yassine et al, 2017).…”

Section: Evidence Of Effective Prevention Strategiesmentioning

confidence: 98%

Aging, cognitive decline, apolipoprotein E and docosahexaenoic acid metabolism

Plourde

2018

OCL

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-In Canada, ∼17 millions of adults between 30-64 years old could benefit from a prevention strategy to lower the risk of Alzheimer's disease (AD). My group is working on a population that is particularly at risk of AD, the carriers of an epsilon 4 allele of apolipoprotein E (E4), a genetic risk. Around 20% of the population in industrial countries have this genetic risk but not all carriers will develop AD, suggesting that environmental factors modulate the clinical manifestation and risk of AD in the carriers. My group has discovered that the metabolism of docosahexaenoic acid (DHA) is disrupted during aging and in E4 carriers, a finding replicated in homozygous mice knocked-in for human E4 allele (hAPOE4). We recently showed that a diet containing DHA prevented behavioral deficits in hAPOE4 mice. Another group reported in E4 carriers that the ratio of arachidonic acid (ARA): DHA is disrupted in the plasma and constitute a preclinical marker of mild cognitive impairment/AD in E4 carriers. Using our kinetics approaches with uniformly labelled carbon 13 fatty acids, we showed that the kinetics of 13 C-DHA is modified by age and E4 carriage. The kinetics of 13 C-arachidonic acid was however not modified by age conversely to that of 13 C-eicosapentaenoic acid (EPA). We also reported that the synthesis of 13 C-DHA from 13 C-EPA started 2 h after the tracer intake in older adults conversely to 7 d in young men. Whether old men needs in DHA is higher or whether their ability to use it is lower remains to be established. These differences in the DHA and EPA metabolism seems, however related to physiological modifications occurring during aging and in E4 carriers and obscure the relationship between plasma DHA and EPA levels, dietary fatty fish intake and cognitive status.Keywords: docosahexaenoic acid / arachidonic acid / eicosapentaenoic acid / aging / cognitive decline / apolipoprotein E / kinetics Résumé -Vieillissement, déclin cognitif, apolipoprotéine E et métabolisme de l'acide docosahexaénoïque. Au Canada, 17 millions d'adultes âgés entre 30-64 ans pourraient bénéficier d'une intervention en prévention pour diminuer leur risque de développer la maladie d'Alzheimer (MA). L'un des groupes les plus à risque de développer la MA, les porteurs de l'allèle epsilon 4 de l'apolipoprotéine E (E4), est au centre des recherches menées par mon groupe. Environ 20 % de la population des pays industrialisés sont porteurs d'E4 mais ce ne sont pas tous les porteurs qui développeront la MA, ce qui suggère que des facteurs environnementaux puissent moduler l'expression clinique et le risque de la MA chez les porteurs. Nous avons découvert que le métabolisme de l'acide docosahexaénoïque (DHA) est débalancé pendant le vieillissement et chez les porteurs de l'E4. Ces découvertes ont été répliquées dans un modèle de souris transgénique dont l'apolipoprotein de souris a été remplacé par de l'E4 humaine (hAPOE4). Nous avons récemment montré qu'une diète riche en DHA prévenait les déficits comportementaux chez la souris hAPOE4. U...

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APOE ε4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical Mild Cognitive Impairment/Alzheimer’s Disease

Cited by 44 publications

References 67 publications

Altered SPMs and age‐associated decrease in brain DHA inAPOE4female mice

Altered SPMs and age‐associated decrease in brain DHA inAPOE4female mice

EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerŉs disease

Aging, cognitive decline, apolipoprotein E and docosahexaenoic acid metabolism

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