Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
Department of Pharmacy, The First People's Hospital of Jingmen, Jingmen, 448000, Hubei, China.
J Mol Neurosci. 2021 Jun;71(6):1306-1319. doi: 10.1007/s12031-020-01758-7. Epub 2021 Jan 6.
The existence of Gram-negative bacteria in the brain, regardless of underlying immune status has been demonstrated by recent studies. The colocalization of lipopolysaccharide (LPS) with Aβ in amyloid plaques supports the hypothesis that brain microbes may be the cause, triggering chronic neuroinflammation, leading to Alzheimer's disease (AD). To investigate the behavioral changes induced by infectious neuroinflammation, we chose the third ventricle as the site of a single LPS injection (20 μg or 80 μg) in male Wistar rats to avoid mechanical injury to forebrain structures while inducing widespread inflammation throughout the brain. Chronic neuroinflammation induced by LPS resulted in depressive-like behaviors and the impairment of spatial learning; however, there was no evidence of the development of pathological hallmarks (e.g., the phosphorylation of tau) for 10 months following LPS injection. The acceleration of cholesterol metabolism via CYP46A1 and the retardation of cholesterol synthesis via HMGCR were observed in the hippocampus of rats treated with either low-dose or high-dose LPS. The rate-limiting enzymes of cholesterol metabolism (CYP46A1) in SH-SY5Y cells and synthesis (HMGCR) in U251 cells were altered by inflammation stimulators, including LPS, IL-1β, and TNF-α, through the TLR4/MyD88/NF-κB signaling pathway. The data suggest that chronic neuroinflammation provoked by the administration of LPS into the third ventricle may induce depressive-like symptoms and that the loss of cholesterol might be a biomarker of chronic neuroinflammation. The lack of pathological hallmarks of AD in our model indicates that Gram-negative bacteria infection might not be a single cause of AD.
最近的研究表明，大脑中革兰氏阴性菌的存在，无论其潜在的免疫状态如何，都已得到证实。脂多糖（LPS）与淀粉样斑块中的 Aβ 的共定位支持了这样一种假设，即大脑微生物可能是导致慢性神经炎症的原因，从而引发阿尔茨海默病（AD）。为了研究传染性神经炎症引起的行为变化，我们选择第三脑室作为单次 LPS 注射（20μg 或 80μg）的部位，在雄性 Wistar 大鼠中，这样可以避免对前脑结构造成机械损伤，同时在整个大脑中引发广泛的炎症。LPS 诱导的慢性神经炎症导致抑郁样行为和空间学习能力受损；然而，在 LPS 注射后 10 个月，没有证据表明出现病理性特征（例如 tau 的磷酸化）。在接受低剂量或高剂量 LPS 治疗的大鼠海马体中观察到胆固醇代谢通过 CYP46A1 加速和胆固醇合成通过 HMGCR 减缓。炎症刺激物（包括 LPS、IL-1β 和 TNF-α）通过 TLR4/MyD88/NF-κB 信号通路改变了 SH-SY5Y 细胞中胆固醇代谢的限速酶（CYP46A1）和 U251 细胞中胆固醇合成的限速酶（HMGCR）。数据表明，向第三脑室注入 LPS 引起的慢性神经炎症可能会引起抑郁样症状，而胆固醇的丧失可能是慢性神经炎症的生物标志物。我们的模型中没有 AD 的病理性特征表明革兰氏阴性菌感染可能不是 AD 的单一原因。
