Zhao Xiaoduo, Yu Jiayi, Xu Bin, Xu Zhi, Lei Xia, Han Shilong, Luo Shangfei, Zhang Can, Peng Guoping, Li Jing, Yu Jie, Ling Yi, Fan Zhongqin, Mo Wei, Yang Ying, Zhang Jing
Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang, China.
Alzheimers Dement. 2025 Aug;21(8):e70331. doi: 10.1002/alz.70331.
Growing evidence links gut microbiota (GM) to Alzheimer's disease (AD). Elevated lipopolysaccharide (LPS) levels, a Gram-negative bacteria component, are found in AD brains, but how LPS breaches the blood-brain barrier (BBB) remains unclear. Hypotheses suggest that bacteria-derived extracellular vesicles (bEVs) may transport LPS across the BBB.
bEVs were extracted from human and mouse feces and blood, and LPS levels were measured. In vivo imaging and immunofluorescence confirmed the transport of blood LPS-carrying bEVs across the BBB. The role of these bEVs in microglia was investigated both in vivo and in vitro.
Elevated LPS-containing bEVs were detected in the plasma of AD patients compared to healthy individuals. These bEVs activated microglial Piezo1, consequently precipitating an excessive synaptic pruning process mediated by the C1q-C3 complement pathway.
These findings illuminate the complex interplay between the gut microbiota, bEVs, neuroinflammation, and synaptic plasticity - a key early event in AD - offering insights for potential therapeutic interventions.
GM-derived bEVs can traverse the BBB. LPS was necessary for bEVs' penetration into the brain, and bEVs might be closely related to AD progression. bEVs mediated microglial activation and synaptic pruning via C1q-C3 complement pathway. Microglia Piezo1 was involved in bEV-induced excessive synaptic pruning.
越来越多的证据表明肠道微生物群（GM）与阿尔茨海默病（AD）有关。在AD患者大脑中发现革兰氏阴性菌成分脂多糖（LPS）水平升高，但LPS如何突破血脑屏障（BBB）仍不清楚。有假说认为细菌衍生的细胞外囊泡（bEVs）可能将LPS转运穿过血脑屏障。
从小鼠和人类粪便及血液中提取bEVs，并测量LPS水平。体内成像和免疫荧光证实携带血液LPS的bEVs可穿过血脑屏障。在体内和体外研究了这些bEVs在小胶质细胞中的作用。
与健康个体相比，AD患者血浆中检测到含LPS的bEVs水平升高。这些bEVs激活小胶质细胞的Piezo1，从而引发由C1q - C3补体途径介导的过度突触修剪过程。
这些发现揭示了肠道微生物群、bEVs、神经炎症和突触可塑性（AD中的一个关键早期事件）之间的复杂相互作用，为潜在的治疗干预提供了见解。
GM衍生的bEVs可以穿过血脑屏障。LPS是bEVs进入大脑所必需的，并且bEVs可能与AD进展密切相关。bEVs通过C1q - C3补体途径介导小胶质细胞激活和突触修剪。小胶质细胞Piezo1参与bEV诱导的过度突触修剪。
