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阿尔茨海默病大鼠大脑中的早期代谢变化由GLAST+细胞驱动。

Early metabolic changes in the brain of Alzheimer's disease rats are driven by GLAST+ cells.

作者信息

Morrey William J, Ceyzériat Kelly, Amossé Quentin, Badina Aurélien M, Dickie Ben, Schiessl Ingo, Tsartsalis Stergios, Millet Philippe, Boutin Hervé, Tournier Benjamin B

机构信息

Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance & University of Manchester, Manchester, UK.

出版信息

J Cereb Blood Flow Metab. 2025 Feb 7:271678X251318923. doi: 10.1177/0271678X251318923.

DOI:10.1177/0271678X251318923
PMID:39917849
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11806453/
Abstract

Glucose metabolic dysfunction is a hallmark of Alzheimer's disease (AD) pathology and is used to diagnose the disease or predict imminent cognitive decline. The main method to measure brain metabolism is positron emission tomography with 2-Deoxy-2-[F]fluoroglucose ([F]FDG-PET). The cellular origin of changes in the [F]FDG-PET signal in AD is controversial. We addressed this by combining [F]FDG-PET with subsequent cell-sorting and γ-counting of [F]FDG-accumulation in sorted cell populations. 7-month-old male TgF344-AD rats and wild-type controls (n = 24/group) received sham or ceftriaxone (200 mg/kg) injection prior to [F]FDG-PET imaging to increase glutamate uptake and glucose utilisation. The same animals were injected again one week later, and radiolabelled brains were dissected, with hippocampi taken for magnetically-activated cell sorting of radioligand-treated tissues (MACS-RTT). Radioactivity in sorted cell populations was measured to quantify cell-specific [F]FDG uptake. Transcriptional analyses of metabolic enzymes/transporters were also performed. metabolism in the frontal association cortex of TgF344-AD rats was identified using [F]FDG-PET, whereas metabolism was identified in the hippocampus using MACS-RTT. Hypermetabolism was primarily driven by GLAST+ cells. This was supported by transcriptional analyses which showed alteration to metabolic apparatus, including upregulation of hexokinase 2 and altered expression of glucose/lactate transporters. See Figure 1 for summary.

摘要

葡萄糖代谢功能障碍是阿尔茨海默病（AD）病理的一个标志，可用于诊断该疾病或预测即将发生的认知衰退。测量脑代谢的主要方法是使用2-脱氧-2-[F]氟葡萄糖（[F]FDG）的正电子发射断层扫描（[F]FDG-PET）。AD中[F]FDG-PET信号变化的细胞起源存在争议。我们通过将[F]FDG-PET与随后的细胞分选以及对分选细胞群体中[F]FDG积累的γ计数相结合来解决这个问题。7个月大的雄性TgF344-AD大鼠和野生型对照（每组n = 24）在进行[F]FDG-PET成像之前接受假手术或头孢曲松（200 mg/kg）注射，以增加谷氨酸摄取和葡萄糖利用。一周后对相同的动物再次注射，然后解剖放射性标记的大脑，取出海马体用于放射性配体处理组织的磁激活细胞分选（MACS-RTT）。测量分选细胞群体中的放射性以量化细胞特异性[F]FDG摄取。还进行了代谢酶/转运蛋白的转录分析。使用[F]FDG-PET确定TgF344-AD大鼠额叶联合皮质中的代谢，而使用MACS-RTT确定海马体中的代谢。高代谢主要由GLAST +细胞驱动。转录分析支持了这一点，其显示代谢装置发生改变，包括己糖激酶2上调以及葡萄糖/乳酸转运蛋白表达改变。总结见图1。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/9c4587b2e91b/10.1177_0271678X251318923-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/ea3489fb3d02/10.1177_0271678X251318923-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/e9d76e85257b/10.1177_0271678X251318923-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/aff3c2ae2e42/10.1177_0271678X251318923-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/7e12e070dc47/10.1177_0271678X251318923-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/7303e9428ddd/10.1177_0271678X251318923-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/e2569cdb028f/10.1177_0271678X251318923-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/9c4587b2e91b/10.1177_0271678X251318923-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/ea3489fb3d02/10.1177_0271678X251318923-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/e9d76e85257b/10.1177_0271678X251318923-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/aff3c2ae2e42/10.1177_0271678X251318923-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/7e12e070dc47/10.1177_0271678X251318923-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/7303e9428ddd/10.1177_0271678X251318923-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/e2569cdb028f/10.1177_0271678X251318923-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d62/11806453/9c4587b2e91b/10.1177_0271678X251318923-fig7.jpg

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本文引用的文献

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Early altered directionality of resting brain network state transitions in the TgF344-AD rat model of Alzheimer's disease.在阿尔茨海默病的TgF344-AD大鼠模型中，静息脑网络状态转换的早期方向性改变。
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Comment on "Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases".评“小胶质细胞激活状态驱动神经退行性疾病中的葡萄糖摄取和 FDG-PET 改变”一文。
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Neurochemical and cognitive changes precede structural abnormalities in the TgF344-AD rat model.在TgF344-AD大鼠模型中，神经化学和认知变化先于结构异常出现。
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