Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Redox Biol. 2023 Jun;62:102690. doi: 10.1016/j.redox.2023.102690. Epub 2023 Mar 27.
The brain is particularly susceptible to oxidative damage which is a key feature of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The shuttling of glutathione (GSH) precursors from astrocytes to neurons has been shown to be instrumental for the neuroprotective activity. Here, we revealed that short chain fatty acids (SCFA), which have been related to AD and PD, could promote glutamate-glutamine shuttle to potentially resist oxidative damage in neurons at cellular level. Furthermore, we performed nine-month-long dietary SCFA supplementations in APPswe/PS1dE9 (APP/PS1) mice, and showed that it reshaped the homeostasis of microbiota and alleviated the cognitive impairment by reducing Aβ deposition and tau hyperphosphorylation. Single-cell RNA sequencing analysis of the hippocampus revealed SCFA can enhance astrocyte-neuron communication including glutamate-glutamine shuttle, mainly by acting on astrocyte in vivo. Collectively, our findings indicate that long-term dietary SCFA supplementations at early aging stage can regulate the neuroenergetics to alleviate AD, providing a promising direction for the development of new AD drug.
大脑特别容易受到氧化损伤的影响，氧化损伤是几种神经退行性疾病的一个关键特征，包括阿尔茨海默病（AD）、帕金森病（PD）和亨廷顿病。已经表明，将谷胱甘肽（GSH）前体从星形胶质细胞运送到神经元对于神经保护活性至关重要。在这里，我们揭示了与 AD 和 PD 相关的短链脂肪酸（SCFA）可以促进谷氨酸-谷氨酰胺穿梭，从而在细胞水平上潜在地抵抗神经元的氧化损伤。此外，我们在 APPswe/PS1dE9（APP/PS1）小鼠中进行了长达九个月的 SCFA 饮食补充，结果表明它通过减少 Aβ 沉积和 tau 过度磷酸化重塑了微生物组的平衡，并减轻了认知障碍。对海马体的单细胞 RNA 测序分析表明，SCFA 可以增强星形胶质细胞-神经元通讯，包括谷氨酸-谷氨酰胺穿梭，主要通过体内作用于星形胶质细胞。总的来说，我们的研究结果表明，在早期衰老阶段长期进行 SCFA 饮食补充可以调节神经能量代谢，从而缓解 AD，为开发新的 AD 药物提供了有前景的方向。
