Kurano Makoto, Saito Yuko, Uranbileg Baasanjav, Saigusa Daisuke, Kano Kuniyuki, Aoki Junken, Yatomi Yutaka
Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Tokyo Metropolitan Geriatric Hospital, Institute of Gerontology, Tokyo, Japan.
Front Aging Neurosci. 2022 Dec 9;14:1066578. doi: 10.3389/fnagi.2022.1066578. eCollection 2022.
Analyses of brain samples from Alzheimer's disease (AD) patients may be expected to help us improve our understanding of the pathogenesis of AD. Bioactive lipids, including sphingolipids, glycerophospholipids, and eicosanoids/related mediators have been demonstrated to exert potent physiological actions and to be involved in the pathogenesis of various human diseases. In this cross-sectional study, we attempted to elucidate the associations of these bioactive lipids with the pathogenesis/pathology of AD through postmortem studies of human brains.
We measured the levels of glycerophospholipids, sphingolipids, and eicosanoids/related mediators in the brains of patients with AD (AD brains), patients with Cerad score B (Cerad-b brains), and control subjects (control brains), using a liquid chromatography-mass spectrometry method; we also measured the mRNA levels of specific receptors for these bioactive lipids in the same brain specimens.
The levels of several species of sphingomyelins and ceramides were higher in the Cerad-b and AD brains. Levels of several species of lysophosphatidic acids (LPAs), lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine (LPE), lysophosphatidylinositol, phosphatidylcholine, phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol, and phosphatidylglycerol were especially high in the Cerad-b brains, while those of lysophosphatidylglycerol (LPG) were especially high in the AD brains. Several eicosanoids, including metabolites of prostaglandin E2, oxylipins, metabolites of epoxide, and metabolites of DHA and EPA, such as resolvins, were also modulated in the AD brains. Among the lipid mediators, the levels of S1P2, S1P5, LPA1, LPA2, LPA6, P2Y10, GPR174, EP1, DP1, DP2, IP, FP, and TXA2r were lower in the AD and/or Cerad-b brains. The brain levels of ceramides, LPC, LPI, PE, and PS showed strong positive correlations with the Aβ contents, while those of LPG showed rather strong positive correlations with the presence of senile plaques and neurofibrillary tangles. A discriminant analysis revealed that LPG is especially important for AD and the LPE/PE axis is important for Cerad-b.
Comprehensive lipidomics, together with the measurement of lipid receptor expression levels provided novel evidence for the associations of bioactive lipids with AD, which is expected to facilitate future translational research and reverse translational research.
对阿尔茨海默病（AD）患者脑样本的分析有望帮助我们加深对AD发病机制的理解。生物活性脂质，包括鞘脂、甘油磷脂和类花生酸/相关介质，已被证明具有强大的生理作用，并参与多种人类疾病的发病机制。在这项横断面研究中，我们试图通过对人脑的尸检研究来阐明这些生物活性脂质与AD发病机制/病理的关联。
我们使用液相色谱-质谱法测量了AD患者脑（AD脑）、Cerad评分B级患者脑（Cerad-b脑）和对照受试者脑（对照脑）中甘油磷脂、鞘脂和类花生酸/相关介质的水平；我们还测量了同一脑标本中这些生物活性脂质特异性受体的mRNA水平。
在Cerad-b脑和AD脑中，几种鞘磷脂和神经酰胺的水平较高。几种溶血磷脂酸（LPA）、溶血磷脂酰胆碱、溶血磷脂酰丝氨酸、溶血磷脂酰乙醇胺（LPE）、溶血磷脂酰肌醇、磷脂酰胆碱、磷脂酰丝氨酸（PS）、磷脂酰乙醇胺（PE）、磷脂酰肌醇和磷脂酰甘油的水平在Cerad-b脑中尤其高，而溶血磷脂酰甘油（LPG）的水平在AD脑中尤其高。几种类花生酸，包括前列腺素E2的代谢产物、氧化脂质、环氧化物的代谢产物以及DHA和EPA的代谢产物，如消退素，在AD脑中也受到调节。在脂质介质中，S1P2、S1P5、LPA1、LPA2、LPA6、P2Y10、GPR174、EP1、DP1、DP2、IP、FP和TXA2r的水平在AD和/或Cerad-b脑中较低。神经酰胺、LPC、LPI、PE和PS的脑水平与Aβ含量呈强正相关，而LPG的脑水平与老年斑和神经原纤维缠结的存在呈较强正相关。判别分析显示，LPG对AD尤为重要，而LPE/PE轴对Cerad-b尤为重要。
综合脂质组学以及脂质受体表达水平的测量为生物活性脂质与AD的关联提供了新证据，有望促进未来的转化研究和反向转化研究。
