Accumulation of Cerebrospinal Fluid Glycerophospholipids and Sphingolipids in Cognitively Healthy Participants With Alzheimer's Biomarkers Precedes Lipolysis in the Dementia Stage.
Accumulation of Cerebrospinal Fluid Glycerophospholipids and Sphingolipids in Cognitively Healthy Participants With Alzheimer's Biomarkers Precedes Lipolysis in the Dementia Stage.
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DOI：
10.3389/fnins.2020.611393
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发表时间：
2020
影响因子：
4.3
通讯作者：
Harrington MG
中科院分区：
文献类型：
--
作者：
Fonteh AN;Chiang AJ;Arakaki X;Edminster SP;Harrington MG
对脂质在阿尔茨海默病（AD）病理生理学中的作用的了解有限，因为在认知健康（CH）个体中尚未对脑膜脂质进行特征描述。由于年龄是AD的一个重要风险因素，我们假设由于膜脂质的恶化，衰老使淀粉样前体蛋白（APP）更容易受到异常加工的影响。为了反映脑膜，我们研究了脑脊液（CSF）及其脑源性CSF纳米颗粒膜中的脂质成分。基于CSF中Aβ42/ Tau水平这一已确定的AD生物标志物，我们定义了Aβ42/ Tau正常的一部分CH参与者（CH - NAT）以及Aβ42/ Tau异常或病理性的另一组（CH - PAT）。我们报告说，甘油磷脂在来自CH - NAT、CH - PAT和AD参与者的CSF上清液和纳米颗粒膜组分中的代谢存在差异。来自CH - PAT上清液组分的磷脂酰胆碱分子种类比CH - NAT和AD参与者中的更高。CH - PAT和AD中上清液组分的鞘磷脂水平比CH - NAT组更低。在AD中，鞘磷脂的减少与神经酰胺和二氢神经酰胺的增加以及神经酰胺与鞘磷脂比率的增加相对应。与上清液组分相反，来自CH - PAT组的纳米颗粒组分中的鞘磷脂更高，同时与CH - NAT相比，CH - PAT中的神经酰胺和二氢神经酰胺更低，神经酰胺与鞘磷脂的比率降低。在研究AD中脂质变化的机制时，我们观察到AD组的磷脂酶A2（PLA2）活性比CH组更高。矛盾的是，与CH组相比，AD组的酸性和中性鞘磷脂酶（SMase）活性更低。考虑到对脂质的外部影响，临床组在空腹血脂或膳食脂质方面没有差异，这与源自脑病理生理学的CSF脂质变化一致。在前驱AD生物标志物阳性阶段的脂质积累确定了脂质代谢的紊乱以及APP/淀粉样β（Aβ）的紊乱是AD病理生理学中的早期事件。我们的结果确定了具有AD生物标志物的CH参与者中脂质周转增加，在痴呆症中转变为以脂解为主的状态。这一知识可能有助于针对和测试新的AD治疗方法。
Insight into lipids’ roles in Alzheimer’s disease (AD) pathophysiology is limited because brain membrane lipids have not been characterized in cognitively healthy (CH) individuals. Since age is a significant risk factor of AD, we hypothesize that aging renders the amyloid precursor protein (APP) more susceptible to abnormal processing because of deteriorating membrane lipids. To reflect brain membranes, we studied their lipid components in cerebrospinal fluid (CSF) and brain-derived CSF nanoparticle membranes. Based on CSF Aβ42/Tau levels established biomarkers of AD, we define a subset of CH participants with normal Aβ42/Tau (CH-NAT) and another group with abnormal or pathological Aβ42/Tau (CH-PAT). We report that glycerophospholipids are differentially metabolized in the CSF supernatant fluid and nanoparticle membrane fractions from CH-NAT, CH-PAT, and AD participants. Phosphatidylcholine molecular species from the supernatant fraction of CH-PAT were higher than in the CH-NAT and AD participants. Sphingomyelin levels in the supernatant fraction were lower in the CH-PAT and AD than in the CH-NAT group. The decrease in sphingomyelin corresponded with an increase in ceramide and dihydroceramide and an increase in the ceramide to sphingomyelin ratio in AD. In contrast to the supernatant fraction, sphingomyelin is higher in the nanoparticle fraction from the CH-PAT group, accompanied by lower ceramide and dihydroceramide and a decrease in the ratio of ceramide to sphingomyelin in CH-PAT compared with CH-NAT. On investigating the mechanism for the lipid changes in AD, we observed that phospholipase A2 (PLA2) activity was higher in the AD group than the CH groups. Paradoxically, acid and neutral sphingomyelinase (SMase) activities were lower in AD compared to the CH groups. Considering external influences on lipids, the clinical groups did not differ in their fasting blood lipids or dietary lipids, consistent with the CSF lipid changes originating from brain pathophysiology. The lipid accumulation in a prodromal AD biomarker positive stage identifies perturbation of lipid metabolism and disturbances in APP/Amyloid beta (Aβ) as early events in AD pathophysiology. Our results identify increased lipid turnover in CH participants with AD biomarkers, switching to a predominantly lipolytic state in dementia. This knowledge may be useful for targeting and testing new AD treatments.
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影响因子：
2.6
作者：
Dursun, Erdinc;Gezen-Ak, Duygu;Yilmazer, Selma
通讯作者：
Yilmazer, Selma
影响因子：
9.9
作者：
Casadei, VM;Ferri, C;Grimaldi, LME
通讯作者：
Grimaldi, LME
影响因子：
4
作者：
Fonteh, Alfred N.;Cipolla, Matthew;Harrington, Michael G.
通讯作者：
Harrington, Michael G.
影响因子：
5.3
作者：
Dinkins, Michael B.;Enasko, John;Bieberich, Erhard
通讯作者：
Bieberich, Erhard
影响因子：
4.7
作者：
Bernoud, N;Fenart, L;Lecerf, J
通讯作者：
Lecerf, J