Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling
Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling
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DOI：
10.1002/alz.12121
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发表时间：
2020-09-01
影响因子：
14
通讯作者：
Willnow, Thomas E.
中科院分区：
文献类型：
--
作者：
Asaro, Antonino;Carlo-Spiewok, Anne-Sophie;Willnow, Thomas E.
载脂蛋白E(ApoE)是脑内脂质的载体，也是阿尔茨海默病(AD)最重要的遗传危险因素。ApoE与受体sortilin结合，后者介导apoE结合的货物被神经元摄取。这种摄取途径对脑脂平衡和AD风险的意义尚不清楚，apoE4而不是apoE3。方法：结合患者样本的神经脂质组学和小鼠模型的功能研究，我们询问了apoE亚型在脑脂代谢和AD中的特定功能。结果：sortilin引导多不饱和脂肪酸的吸收和转化为内源性大麻素，内源性神经递质通过核受体作用，维持脑中神经保护性基因的表达。这种sortilin功能需要apoE3，但会被apoE4的结合破坏，从而影响神经元内源性大麻素的代谢和作用。讨论：我们揭示了神经元apoE受体sortilin在促进脑脂类神经保护作用中的意义，以及它与apoE4的AD风险的相关性。
Introduction: Apolipoprotein E (apoE) is a carrier for brain lipids and the most important genetic risk factor for Alzheimer's disease (AD). ApoE binds the receptor sortilin, which mediates uptake of apoE-bound cargo into neurons. The significance of this uptake route for brain lipid homeostasis and AD risk seen with apoE4, but not apoE3, remains unresolved.Methods: Combining neurolipidomics in patient specimens with functional studies in mouse models, we interrogated apoE isoform-specific functions for sortilin in brain lipid metabolism and AD.Results: Sortilin directs the uptake and conversion of polyunsaturated fatty acids into endocannabinoids, lipid-based neurotransmitters that act through nuclear receptors to sustain neuroprotective gene expression in the brain. This sortilin function requires apoE3, but is disrupted by binding of apoE4, compromising neuronal endocannabinoid metabolism and action.Discussion: We uncovered the significance of neuronal apoE receptor sortilin in facilitating neuroprotective actions of brain lipids, and its relevance for AD risk seen with apoE4.