Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice

Abstract

Apolipoprotein E ε4 (APOE4) is the primary genetic risk factor for the late-onset form of Alzheimer’s disease (AD). Although the reason for this association is not completely understood, researchers have uncovered numerous effects of APOE4 expression on AD-relevant brain processes, including amyloid beta (Aβ) accumulation, lipid metabolism, endosomal-lysosomal trafficking, and bioenergetics. In this study, we aimed to determine the effect of APOE4 allelic dosage on regional brain lipid composition in aged mice, as well as in cultured neurons. We performed a targeted lipidomic analysis on an AD-vulnerable brain region (entorhinal cortex; EC) and an AD-resistant brain region (primary visual cortex; PVC) from 14–15 month-old APOE3/3, APOE3/4, and APOE4/4 targeted replacement mice, as well as on neurons cultured with conditioned media from APOE3/3 or APOE4/4 astrocytes. Our results reveal that the EC possesses increased susceptibility to APOE4-associated lipid alterations compared to the PVC. In the EC, APOE4 expression showed a dominant effect in decreasing diacylglycerol (DAG) levels, and a semi-dominant, additive effect in the upregulation of multiple ceramide, glycosylated sphingolipid, and bis(monoacylglycerol)phosphate (BMP) species, lipids known to accumulate as a result of endosomal-lysosomal dysfunction. Neurons treated with conditioned media from APOE4/4 vs. APOE3/3 astrocytes showed similar alterations of DAG and BMP species to those observed in the mouse EC. Our results suggest that APOE4 expression differentially modulates regional neuronal lipid signatures, which may underlie the increased susceptibility of EC-localized neurons to AD pathology.

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

“…Targeted lipidomic analysis in APOE knock-in mice have evidenced a higher susceptibility of lipidic alterations in the entorhinal cortex (EC) of APOE4 mice [ 135 ]. Shotgun lipidomic studies in the parietal lobe of AD brains from APOE2 , APOE3 and APOE4 carriers evidenced significantly lower phospholipid levels in APOE4 carriers and marked differences in the brain lipidomes between APOE3 /3 and APOE4 carriers [ 136 ].…”

How Alpha Linolenic Acid May Sustain Blood–Brain Barrier Integrity and Boost Brain Resilience against Alzheimer’s Disease

“…Interestingly, studies in a population with large-vessel disease show altered serum lipid profile in ApoE4 carriers, compared with ApoE2 and ApoE3 [ 80 ]. ApoE4 mice have shown increased susceptibility to endothelial cells lipid alterations [ 81 ], involving intracellular lipid flux and lipid droplet regulation as potential factors underlying higher AD risk [ 82 ]. These findings further support a role for lipid disarray in neurodegeneration and suggest nutritional modulation as a potentially efficacious therapeutic strategy in ApoE4 carriers [ 83 ].…”

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

“…A handful of previous studies have examined the role of human APOE on the mouse brain transcriptome and metabolome, 28 - 32 and a recent study inferred strong, glial-driven APOE genotype effects from whole-tissue bulk RNA-seq of postmortem human brains. 33 Together these important studies highlight both amyloid-dependent and -independent roles for APOE, age, and brain region in metabolic and immune changes.…”