Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer's dementia

Abstract

Background: Chronic neuroinflammation is one of the hallmarks of late-onset Alzheimer's disease (AD) dementia pathogenesis. Carrying the apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration.

Methods: Using brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified by APOE genotype.

Results: Lipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. A significant interaction was observed between carrying the APOE4 allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium-dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and soluble epoxide hydrolase (sEH) enzymes.

Conclusion: These findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, which is increased in carriers of the APOE4 allele, and identify potential therapeutic targets for resolving this chronic inflammatory state.

Keywords: Alzheimer’s disease; ApoE; Inflammation; Lipidomics.

Fig. 1

PUFAs, eicosanoids, and specialized pro-resolving lipid mediators (SPMs) and their regulation by phospholipase A2, 5-LOX, and sEH enzymes. ApoE4 sustains cPLA2 activation more than ApoE3. Red squares represent inflammatory components, while blue squares represent pro-resolving mediators. White squares are analytes where biological activity has not been clearly ascertained. Abbreviations: cPLA2, calcium-dependent phospholipase A2; iPLA2, calcium-independent phospholipase A2; AA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; PGs, prostaglandins; TXs, thromboxanes; 12-HHT, 12-hydroxyheptadecatrienoic acid; HETEs, hydroxyeicosatetraenoic acids; HEPEs, hydroxyeicosapentaenoic acids; HDHAs, hydroxydocosahexaenoic acids; LTs, leukotrienes; LXs, lipoxins; EETs, epoxyeicosatrienoic acids; DHETs, dihydroxyeicosatrienoic acids; RvEs, E-series resolvins, MaRs, maresins; RvDs, D-series resolvins; NPDs, neuroprotectins; 5-LOX, 5-lipoxygenase; sEH, soluble epoxide hydrolase

Fig. 2

Dysregulation of bioactive lipids in the Alzheimer’s disease dementia brain evidenced by lower levels of ω-3: ω-6 fatty acids and pro-resolving lipid mediator NPD1. * p < 0.05, ** p < 0.01, *** p < 0.001; two-tailed Student’s t test. Abbreviations: AA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; NPD1, neuroprotectin D1. Samples per group: NCI male 3/3 (N=6), NCI male 3/4 (N=4), NCI female 3/3 (N=6), NCI female 3/4 (N=5), AD male 3/3 (N=7), AD male 3/4 (N=3), AD female 3/3 (N=5), AD female 3/4 (N=6)

Fig. 3

AD dementia brains from APOE4 carriers display higher levels of pro-inflammatory and pro-resolving mediator lipids indicating chronic unresolved inflammation. * p < 0.05, ** p < 0.01, *** p < 0.001; p-values for β-estimates were derived from the regression model adjusted for age and education. Abbreviations: AA, arachidonic acid; 5-HETE, 5-hydroxyeicosatetraenoic acid; PGs, prostaglandins; TXB2, thromboxane B2; 12-HHT, 12-hydroxyheptadecatrienoic acid; LXs, lipoxins; LTB4, leukotriene B4; EPA, eicosapentaenoic acid; 5-HEPE, 5-hydroxyeicosapentaenoic acid; RvE3, resolvin E3; DHA, docosahexaenoic acid; 17-HDHA, 17-hydroxydocosahexaenoic acid; RvDs, D-series resolvins; NPD-1, neuroprotectin D1; DPA, docosapentaenoic acid

Fig. 4

A Correlation matrices illustrate the relationships between cortical lipid levels and clinical and AD neuropathology phenotypes, which are exaggerated in APOE4 carriers. Color-coded scale from -1.0 to 1.0 denotes the relative intensities of spearman correlation coefficients (r_s). B Interaction effects between some of lipid mediator levels and APOE4 on global cognitive function (C) and neuritic plaque burden. Abbreviations: AA, arachidonic acid; 5-HETE, 5-hydroxyeicosatetraenoic acid; PGs, prostaglandins; TXB2, thromboxane B2; 12-HHT, 12-hydroxyheptadecatrienoic acid; LXs, lipoxins; LTB4, leukotriene B4; EPA, eicosapentaenoic acid; 5-HEPE, 5-hydroxyeicosapentaenoic acid; RvE3, resolvin E3; DHA, docosahexaenoic acid; 17-HDHA, 17-hydroxydocosahexaenoic acid; RvDs, D-series resolvins; NPD-1, neuroprotectin D1; DPA, docosapentaenoic acid; NFT, Neurofibrillary tangles. P values represent the interaction of APOE genotype and lipid mediators on global cognitive function and neuritic plaque burden

Fig. 5

A Increased 5-LOX activity surrogates in brains with AD dementia. B Decreased soluble epoxide hydrolase (sEH) activity surrogates in brains with AD dementia. * p < 0.05, ** p < 0.01, *** p < 0.001; two-tailed Student’s t test. C Inverse relationship between sEH activity and LXA4 production in brains with AD and NCI on linear (left) and log-scale (right). EPA, eicosapentaenoic acid; HETEs, hydroxyeicosatetraenoic acids; HEPEs, hydroxyeicosapentaenoic acids; 17-HDHAs, 17-hydroxydocosahexaenoic acid, LXA4, lipoxin A4; EETs, epoxyeicosatrienoic acids; DHETs, dihydroxyeicosatrienoic acids; RvEs, E-series resolvins, RvDs, D-series resolvins; NPDs, neuroprotectins