Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice.
Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice.
复制标题
APOE4等位基因剂量对老年小鼠内嗅皮层脂质组学特征的影响。
DOI：
10.1038/s41398-022-01881-6
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发表时间：
2022-03-29
影响因子：
6.8
通讯作者：
Nuriel T
中科院分区：
文献类型：
--
作者：
Miranda AM;Ashok A;Chan RB;Zhou B;Xu Y;McIntire LB;Area-Gomez E;Di Paolo G;Duff KE;Oliveira TG;Nuriel T
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.
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影响因子：
16.6
作者：
Fitz NF;Nam KN;Wolfe CM;Letronne F;Playso BE;Iordanova BE;Kozai TDY;Biedrzycki RJ;Kagan VE;Tyurina YY;Han X;Lefterov I;Koldamova R
通讯作者：
Koldamova R
DOI：
10.1038/nrm.2017.107
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Hannun YA;Obeid LM
通讯作者：
Obeid LM
对人类、黑猩猩、猕猴和小鼠组织的大规模分析揭示了脑脂质组的组织和进化
影响因子：
16.2
作者：
Bozek, Katarzyna;Wei, Yuning;Khaitovich, Philipp
通讯作者：
Khaitovich, Philipp
影响因子：
4.8
作者：
Chan, Robin B.;Oliveira, Tiago G.;Di Paolo, Gilbert
通讯作者：
Di Paolo, Gilbert
影响因子：
4.6
作者：
Area-Gomez, Estela;Larrea, Delfina;Nuriel, Tal
通讯作者：
Nuriel, Tal