LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
Department of Cell Biology and Anatomy, LSU Health Science Center, New Orleans, LA 70112, USA.
Int J Mol Sci. 2022 Oct 21;23(20):12671. doi: 10.3390/ijms232012671.
Lipopolysaccharides (LPSs) are microbiome-derived glycolipids that are among the most potent pro-inflammatory neurotoxins known. In , the major sources of LPSs are gastrointestinal (GI)-tract-resident facultative anaerobic Gram-negative bacilli, including and . 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: 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 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.
脂多糖（LPSs）是微生物群衍生的糖脂，是已知最有效的促炎神经毒素之一。在 ，LPSs 的主要来源是胃肠道（GI）tract 居住的兼性厌氧革兰氏阴性杆菌，包括 和 。多个独立的研究调查人员在衰老的人类大脑中大量检测到 LPSs，并且在受阿尔茨海默病（AD）影响的神经元周围和内部发现 LPSs 的丰度增加。微生物群产生的 LPSs 和其他内毒素穿过 GI-tract 生物物理屏障进入全身循环，并穿过血脑屏障进入大脑，这个病理过程在衰老和血管疾病（包括“肠漏综合征”）期间增加。进一步的证据表明，LPSs 上调促炎转录因子复合物 NF-kB（p50/p65），随后是一组 NF-kB 敏感的 microRNAs，包括 miRNA-30b、miRNA-34a、miRNA-146a 和 miRNA-155。这些上调的 microRNAs 反过来下调一组与神经退行性相关的信使 RNA（mRNA）靶标，包括编码神经元特异性神经丝轻（NF-L）链蛋白的 mRNA。虽然已经报道在 AD 和其他进行性和致命性促炎神经退行性疾病的外周生物流体中 NF-L 上调，但 NF-L 在新皮层神经元内显著下调，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、修改的突触结构和神经元信号转导能力的网络缺陷的原因。本文综述并揭示了 LPSs 的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、与年龄相关的最终致命神经退行性疾病的生物学机制。这个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： 强调了 GI-tract 微生物 LPSs 与 AD 大脑和应激原代培养人脑细胞的炎症神经病理学、紊乱的细胞骨架和破坏的突触信号之间的直接正病理联系； 是第一个微生物群衍生的神经毒性糖脂对 NF-L 表达具有显著有害的 miRNA 介导作用的例子，NF-L 是一种丰富的丝状蛋白，已知对神经元和突触稳态的维持很重要。
