Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.-猫眼课题宝

DOI：

10.1093/brain/awad037

发表时间：

2023-04

期刊：

Brain : a journal of neurology

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Min-Ho Nam;H. Ko;Dongwoo Kim;Sangwon Lee;Yongmin Mason Park;Seung Jae Hyeon;Woojin Won;Jee-in Chung;Seon yoo Kim;Hanhee Jo;Kyeongtaek Oh;Young-eun Han;G. Lee;Y. Ju;Hyowon Lee;Hyunjin Kim;Jaejun Heo;Mridula Bhalla;Ki Jung Kim;Jea Kwon;T. Stein;Mingyu Kong;Hyunbeom Lee;Seung Eun Lee;Soo-Jin Oh;Joong-Hyun Chun;Mi-Ae Park;Ki Duk Park;Hoon Ryu;M. Yun;C. J. Lee

反应性星形胶质细胞增生是阿尔茨海默病（AD）的标志。然而，一个临床验证的神经影像学探针可视化反应性星形胶质细胞增生尚未被发现。在这里，我们表明，PET成像与11 C-乙酸和18 F-氟脱氧葡萄糖（18 F-FDG）功能可视化的反应性星形胶质细胞介导的神经元代谢低下的神经炎症和AD的大脑。为了研究患病大脑中乙酸盐和葡萄糖代谢的改变及其对AD病理学的影响，我们采用了多方面的方法，包括microPET成像，放射自显影，免疫组织化学，代谢组学和电生理学。本研究中使用了两种AD啮齿动物模型，APP/PS1和5xFAD转基因小鼠，一种腺病毒诱导的反应性星形胶质细胞增生大鼠模型和死后人脑组织。我们进一步策划了一项概念验证人体研究，其中包括11 C-醋酸盐和18 F-FDG PET成像分析沿着11例AD患者和10例健康对照受试者的神经心理学评估。我们证明，反应性星形胶质细胞过度吸收乙酸通过升高单羧酸转运蛋白-1（MCT 1）在啮齿动物模型的反应性星形胶质细胞增生和AD。醋酸盐摄取升高与反应性星形胶质细胞增生相关，并在淀粉样蛋白-β存在时促进异常星形胶质细胞GABA合成。过量的星形胶质细胞GABA随后抑制神经元活动，这可能导致葡萄糖摄取通过减少葡萄糖转运蛋白-3在患病的大脑。我们进一步证明，11 C-乙酸摄取显着增加，内嗅皮质，海马和颞顶叶新皮质的AD患者相比，健康对照组，而18 F-FDG摄取显着减少，在相同的地区。此外，我们发现患者的认知功能与11 C-醋酸盐和18 F-FDG的PET信号之间存在很强的相关性。我们通过观察AD患者的反应性星形胶质细胞增生和相关的神经元葡萄糖代谢低下，证明了11 C-醋酸盐和18F-FDG PET成像的潜在价值。我们的研究结果进一步表明，醋酸盐增强的反应性星形胶质细胞-神经元相互作用可能有助于AD的认知能力下降。

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-β is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients' cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.

Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.

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