<br>脂多糖（LPS）作为阿尔茨海默病（AD）中的强效神经毒性糖脂,International Journal of Molecular Sciences

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脂多糖（LPS）作为阿尔茨海默病（AD）中的强效神经毒性糖脂
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2022-10-21 , DOI: 10.3390/ijms232012671
Yuhai Zhao _{1,

2} , Vivian R Jaber ₁ , Aileen I Pogue ₃ , Nathan M Sharfman ₁ , Christopher Taylor ₄ , Walter J Lukiw _{1,

3,

5,

6}

Affiliation

脂多糖（LPS）是微生物组衍生的糖脂，是已知最有效的促炎神经毒素之一。在智人中，LPS 的主要来源是胃肠道（GI）驻留的兼性厌氧革兰阴性杆菌，包括脆弱拟杆菌和大肠杆菌。多个独立研究调查员已在老年的人脑中大量检测到 LPS，并且已发现受阿尔茨海默病（AD）影响的神经元周围和内部的 LPS 丰度增加。微生物组产生的 LPS 和其他内毒素穿过胃肠道生物生理屏障进入体循环，并穿过血脑屏障进入大脑，这一病理过程随着衰老和血管疾病（包括“肠漏综合征”）而增加。进一步的证据表明，LPS 上调促炎转录因子复合物 NF-kB （p50/p65），随后上调一组 NF-kB 敏感的 microRNA，包括 miRNA-30b、miRNA-34a、miRNA-146a 和 miRNA-155。这些上调的 miRNA 反过来下调神经退行性病变相关信使 RNA （mRNA）靶标家族，包括编码神经元特异性神经丝光（NF-L）链蛋白的 mRNA。虽然据报道 NF-L 在 AD 和其他进行性和致命的促炎性神经退行性疾病的外周生物液中上调，但 NF-L 在新皮层神经元中显着下调，这可能是神经元萎缩、轴突口径丧失和神经元细胞形状改变、突触结构修饰和神经元信号传输能力网络缺陷的原因。本文回顾并揭示了有关 LPS 神经毒性方面的最新发现，以及这些促炎糖脂如何导致进行性、年龄相关并最终致命的神经退行性疾病的生物学机制。这种最近发现的肠道微生物群衍生的 LPS-NF-kB-miRNA-30b-NF-L 病理信号网络：（i） 强调了胃肠道微生物的 LPS 与原代培养中 AD 脑和应激人脑细胞的炎症神经病理学、细胞骨架紊乱和突触信号传导中断之间的直接正病理联系;（ii） 是微生物组衍生的神经毒性糖脂对 NF-L 的表达具有显着有害 miRNA 介导的作用的第一个例子，NF-L 是一种丰富的丝状蛋白，已知在维持神经元和突触稳态中很重要。

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Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In Homo sapiens, the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including Bacteroides fragilis and Escherichia coli. LPSs have been abundantly detected in aged human brain by multiple independent research investigators, and an increased abundance of LPSs around and within Alzheimer’s disease (AD)-affected neurons has been found. Microbiome-generated LPSs and other endotoxins cross GI-tract biophysiological barriers into the systemic circulation and across the blood–brain barrier into the brain, a pathological process that increases during aging and in vascular disorders, including ‘leaky gut syndrome’. Further evidence indicates that LPSs up-regulate pro-inflammatory transcription factor complex NF-kB (p50/p65) and subsequently a set of NF-kB-sensitive microRNAs, including miRNA-30b, miRNA-34a, miRNA-146a and miRNA-155. These up-regulated miRNAs in turn down-regulate a family of neurodegeneration-associated messenger RNA (mRNA) targets, including the mRNA encoding the neuron-specific neurofilament light (NF-L) chain protein. While NF-L has been reported to be up-regulated in peripheral biofluids in AD and other progressive and lethal pro-inflammatory neurodegenerative disorders, NF-L is significantly down-regulated within neocortical neurons, and this may account for neuronal atrophy, loss of axonal caliber and alterations in neuronal cell shape, modified synaptic architecture and network deficits in neuronal signaling capacity. This paper reviews and reveals the most current findings on the neurotoxic aspects of LPSs and how these pro-inflammatory glycolipids contribute to the biological mechanism of progressive, age-related and ultimately lethal neurodegenerative disorders. This recently discovered gut-microbiota-derived LPS–NF-kB–miRNA-30b–NF-L pathological signaling network: (i) underscores a direct positive pathological link between the LPSs of GI-tract microbes and the inflammatory neuropathology, disordered cytoskeleton, and disrupted synaptic-signaling of the AD brain and stressed human brain cells in primary culture; and (ii) is the first example of a microbiome-derived neurotoxic glycolipid having significant detrimental miRNA-mediated actions on the expression of NF-L, an abundant filamentous protein known to be important in the maintenance of neuronal and synaptic homeostasis.

更新日期：2022-10-21

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