A Dichotomous Role for FABP7 in Sleep and Alzheimer's Disease Pathogenesis: A Hypothesis.
A Dichotomous Role for FABP7 in Sleep and Alzheimer's Disease Pathogenesis: A Hypothesis.
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DOI：
10.3389/fnins.2022.798994
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发表时间：
2022
影响因子：
4.3
通讯作者：
Gerstner, Jason R.
中科院分区：
文献类型：
--
作者：
Needham, Hope;Torpey, Grace;Flores, Carlos C.;Davis, Christopher J.;Vanderheyden, William M.;Gerstner, Jason R.
脂肪酸结合蛋白 (FABP) 是细胞内脂质伴侣蛋白家族，已知在脂肪酸摄取和转运以及基因表达的调节中发挥关键作用。脑型脂肪酸结合蛋白 (FABP7) 富含于星形胶质细胞中，与睡眠/觉醒调节和神经退行性疾病有关；然而，FABP7 在这些生物过程中作用的确切机制仍不清楚。 FABP7 与花生四烯酸 (AA) 和二十二碳六烯酸 (DHA) 结合，导致离散的生理反应。在这里，我们提出 FABP7 的二分作用，其中配体类型决定脂肪酸的亚细胞易位，要么促进与阿尔茨海默病发病机制相关的觉醒，要么促进睡眠，同时激活抗炎途径和神经保护。我们假设 FABP7 介导的 AA 易位到星形胶质细胞的内质网会增加星形胶质细胞增生，阻碍谷氨酸能摄取，并通过 COX-2 依赖性促炎性前列腺素的生成增强觉醒和炎症途径。相反，我们认为 FABP7 介导的 DHA 易位到细胞核可稳定星形胶质细胞 - 神经元乳酸穿梭动力学，保留谷氨酸能摄取，并通过过氧化物酶体增殖物激活受体 - γ 转录级联激活抗炎途径来促进睡眠。重要的是，该模型产生了几个适用于其他神经退行性疾病的可测试假设，包括肌萎缩侧索硬化症和帕金森病。
Fatty acid binding proteins (FABPs) are a family of intracellular lipid chaperone proteins known to play critical roles in the regulation of fatty acid uptake and transport as well as gene expression. Brain-type fatty acid binding protein (FABP7) is enriched in astrocytes and has been implicated in sleep/wake regulation and neurodegenerative diseases; however, the precise mechanisms underlying the role of FABP7 in these biological processes remain unclear. FABP7 binds to both arachidonic acid (AA) and docosahexaenoic acid (DHA), resulting in discrete physiological responses. Here, we propose a dichotomous role for FABP7 in which ligand type determines the subcellular translocation of fatty acids, either promoting wakefulness aligned with Alzheimer’s pathogenesis or promoting sleep with concomitant activation of anti-inflammatory pathways and neuroprotection. We hypothesize that FABP7-mediated translocation of AA to the endoplasmic reticulum of astrocytes increases astrogliosis, impedes glutamatergic uptake, and enhances wakefulness and inflammatory pathways via COX-2 dependent generation of pro-inflammatory prostaglandins. Conversely, we propose that FABP7-mediated translocation of DHA to the nucleus stabilizes astrocyte-neuron lactate shuttle dynamics, preserves glutamatergic uptake, and promotes sleep by activating anti-inflammatory pathways through the peroxisome proliferator-activated receptor-γ transcriptional cascade. Importantly, this model generates several testable hypotheses applicable to other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson’s disease.
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影响因子：
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通讯作者：
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作者：
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通讯作者：
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