After decades of research recognizing it as a complex multifactorial disorder, sporadic Alzheimer’s disease (sAD) still has no known etiology. Adding to the myriad of different pathways involved, bacterial neurotoxins are assuming greater importance in the etiology and/or progression of sAD. β-N-Methylamino-l-alanine (BMAA), a neurotoxin produced by some microorganisms namely cyanobacteria, was previously detected in the brains of AD patients. Indeed, the consumption of BMAA-enriched foods has been proposed to induce amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), which implicated this microbial metabolite in neurodegeneration mechanisms. Freshly isolated mitochondria from C57BL/6 mice were treated with BMAA and O2 consumption rates were determined. O2 consumption and glycolysis rates were also measured in mouse primary cortical neuronal cultures. Further, mitochondrial membrane potential and ROS production were evaluated by fluorimetry and the integrity of mitochondrial network was examined by immunofluorescence. Finally, the ability of BMAA to activate neuronal innate immunity was quantified by addressing TLRs (Toll-like receptors) expression, p65 NF-κB translocation into the nucleus, increased expression of NLRP3 (Nod-like receptor 3), and pro-IL-1β. Caspase-1 activity was evaluated using a colorimetric substrate and mature IL-1β levels were also determined by ELISA. Treatment with BMAA reduced O2 consumption rates in both isolated mitochondria and in primary cortical cultures, with additional reduced glycolytic rates, decrease mitochondrial potential and increased ROS production. The mitochondrial network was found to be fragmented, which resulted in cardiolipin exposure that stimulated inflammasome NLRP3, reinforced by decreased mitochondrial turnover, as indicated by increased p62 levels. BMAA treatment also activated neuronal extracellular TLR4 and intracellular TLR3, inducing p65 NF-κB translocation into the nucleus and activating the transcription of NLRP3 and pro-IL-1β. Increased caspase-1 activity resulted in elevated levels of mature IL-1β. These alterations in mitochondrial metabolism and inflammation increased Tau phosphorylation and Aβ peptides production, two hallmarks of AD. Here we propose a unifying mechanism for AD neurodegeneration in which a microbial toxin can induce mitochondrial dysfunction and activate neuronal innate immunity, which ultimately results in Tau and Aβ pathology. Our data show that neurons, alone, can mount inflammatory responses, a role previously attributed exclusively to glial cells.

中文翻译：

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微生物 BMAA 在皮质神经元中引发线粒体功能障碍、先天免疫激活和阿尔茨海默病特征

经过数十年的研究，认识到它是一种复杂的多因素疾病，散发性阿尔茨海默病 (sAD) 仍然没有已知的病因。除了所涉及的无数不同途径之外，细菌神经毒素在 sAD 的病因和/或进展中扮演着更重要的角色。β-N-甲基氨基-l-丙氨酸（BMAA）是一种由某些微生物（即蓝藻）产生的神经毒素，以前在 AD 患者的大脑中检测到。事实上，已经提出食用富含 BMAA 的食物会诱发肌萎缩侧索硬化症 - 帕金森症 - 痴呆症复合体 (ALS-PDC)，这表明这种微生物代谢物与神经变性机制有关。用 BMAA 处理来自 C57BL/6 小鼠的新鲜分离的线粒体，并确定 O2 消耗率。还在小鼠原代皮质神经元培养物中测量了 O2 消耗和糖酵解率。此外，通过荧光测定法评估线粒体膜电位和 ROS 产生，并通过免疫荧光检查线粒体网络的完整性。最后，BMAA 激活神经元先天免疫的能力通过解决 TLR（Toll 样受体）表达、p65 NF-κB 易位到细胞核、NLRP3（Nod 样受体 3）和 pro-IL- 表达增加来量化。 1β。使用比色底物评估 Caspase-1 活性，也通过 ELISA 确定成熟的 IL-1β 水平。BMAA 治疗降低了分离线粒体和原代皮质培养物中的 O2 消耗率，另外降低了糖酵解率，降低了线粒体潜能并增加了 ROS 产生。线粒体网络被发现是碎片化的，这导致心磷脂暴露刺激炎性体 NLRP3，线粒体更新减少，如 p62 水平增加所表明的那样。BMAA 治疗还激活神经元胞外 TLR4 和胞内 TLR3，诱导 p65 NF-κB 易位进入细胞核并激活 NLRP3 和 pro-IL-1β 的转录。caspase-1 活性增加导致成熟 IL-1β 水平升高。线粒体代谢和炎症的这些改变增加了 Tau 磷酸化和 Aβ 肽的产生，这是 AD 的两个标志。在这里，我们提出了 AD 神经变性的统一机制，其中微生物毒素可以诱导线粒体功能障碍并激活神经元先天免疫，最终导致 Tau 和 Aβ 病理。