GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment.
GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment.
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GPR39缺乏症会损害记忆力并改变催产素和炎症细胞因子，而不会影响高脂饮食小鼠认知障碍模型中的脑血流。
DOI：
10.3389/fncel.2022.893030
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发表时间：
2022
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
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作者：
血管性认知障碍（VCI）是痴呆的第二大常见原因。目前还没有治疗VCI的方法，部分原因是缺乏对其潜在机制的了解。g蛋白偶联受体39 （GPR39）受花生四烯酸（AA）衍生的氧化脂素调控，这种氧化脂素与VCI有关。此外，GPR39在死后脑VCI的小胶质细胞中表达增加。纯合子GPR39 snp的携带者有更高的白质高强度负担，这是VCI的MRI标记物。我们验证了GPR39对高脂肪饮食（HFD）诱导的认知障碍起保护作用的假设，部分是通过氧化脂素对脑血流量（CBF）和神经炎症的作用介导的。纯合子（KO）和杂合子（Het） GPR39敲除小鼠以及野生型（WT）有或没有HFD的幼崽8个月后，使用新物体识别（NOR）和Morris水迷宫（MWM）测试认知表现，随后使用MRI测量CBF。采用高效液相色谱-质谱联用技术对脑组织和血浆中的氧脂进行定量分析。细胞因子和趋化因子采用多重测定法测定。与WT和ht小鼠相比，无论饮食如何，KO小鼠在MWM中离平台位置游得更远。在NOR试验中，没有基因型或饮食的影响。HFD和GPR39缺失后，由11-和15-脂氧合酶（LOX）、环氧合酶（COX）和非酶促形成的脑和血浆aa衍生的氧脂素增加。白介素-10 （IL-10）水平在高脂饮食组的KO小鼠中低于标准饮食组（STD），而IL-4、干扰素γ诱导蛋白-10 （IP-10）和单核细胞趋化蛋白-3 （MCP-3）水平在WT和KO小鼠中均有改变，但不受基因型的影响。WT和KO小鼠的静息CBF减少，血管反应性无变化。与WT小鼠相比，GPR39的缺失没有改变性病或HFD小鼠的CBF。我们得出结论，GPR39在空间记忆保持中发挥作用，并部分通过调节炎症和aa衍生的氧化脂素来防止hfd诱导的认知障碍。结果表明GPR39和氧化脂素通路在VCI中发挥作用，可能作为治疗靶点。
Vascular cognitive impairment (VCI) is the second most common cause of dementia. There is no treatment for VCI, in part due to a lack of understanding of the underlying mechanisms. The G-protein coupled receptor 39 (GPR39) is regulated by arachidonic acid (AA)-derived oxylipins that have been implicated in VCI. Furthermore, GPR39 is increased in microglia of post mortem human brains with VCI. Carriers of homozygous GPR39 SNPs have a higher burden of white matter hyperintensity, an MRI marker of VCI. We tested the hypothesis that GPR39 plays a protective role against high-fat diet (HFD)-induced cognitive impairment, in part mediated via oxylipins actions on cerebral blood flow (CBF) and neuroinflammation. Homozygous (KO) and heterozygous (Het) GPR39 knockout mice and wild-type (WT) littermates with and without HFD for 8 months were tested for cognitive performance using the novel object recognition (NOR) and the Morris water maze (MWM) tests, followed by CBF measurements using MRI. Brain tissue and plasma oxylipins were quantified with high-performance liquid chromatography coupled to mass spectrometry. Cytokines and chemokines were measured using a multiplex assay. KO mice, regardless of diet, swam further away from platform location in the MWM compared to WT and Het mice. In the NOR test, there were no effects of genotype or diet. Brain and plasma AA-derived oxylipins formed by 11- and 15-lipoxygenase (LOX), cyclooxygenase (COX) and non-enzymatically were increased by HFD and GPR39 deletion. Interleukin-10 (IL-10) was lower in KO mice on HFD than standard diet (STD), whereas IL-4, interferon γ-induced protein-10 (IP-10) and monocyte chemotactic protein-3 (MCP-3) were altered by diet in both WT and KO, but were not affected by genotype. Resting CBF was reduced in WT and KO mice on HFD, with no change in vasoreactivity. The deletion of GPR39 did not change CBF compared to WT mice on either STD or HFD. We conclude that GPR39 plays a role in spatial memory retention and protects against HFD-induced cognitive impairment in part by modulating inflammation and AA-derived oxylipins. The results indicate that GPR39 and oxylipin pathways play a role and may serve as therapeutic targets in VCI.
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载脂蛋白E4介导与胰岛素抵抗相关的脑血管功能障碍和餐后反应。
DOI：
10.1177/0271678x17746186
发表时间：
2019-05
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Johnson LA;Torres ER;Weber Boutros S;Patel E;Akinyeke T;Alkayed NJ;Raber J
通讯作者：
Raber J
DOI：
10.1002/trc2.12214
发表时间：
2021
期刊：
Alzheimer's & dementia (New York, N. Y.)
影响因子：
--
作者：
Davis CM;Bah TM;Zhang WH;Nelson JW;Golgotiu K;Nie X;Alkayed FN;Young JM;Woltjer RL;Silbert LC;Grafe MR;Alkayed NJ
通讯作者：
Alkayed NJ
影响因子：
4.5
作者：
La Frano, Michael R.;Hernandez-Carretero, Angelina;Newman, John W.
通讯作者：
Newman, John W.
影响因子：
3.6
作者：
Le DE;García-Jaramillo M;Bobe G;Alcazar Magana A;Vaswani A;Minnier J;Jump DB;Rinkevich D;Alkayed NJ;Maier CS;Kaul S
通讯作者：
Kaul S
影响因子：
5.6
作者：
Davis CM;Zhang WH;Allen EM;Bah TM;Shangraw RE;Alkayed NJ
通讯作者：
Alkayed NJ