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_1-40/42 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.

最近的研究已经证明，无论潜在的免疫状态如何，大脑中都存在革兰氏阴性菌。脂多糖 (LPS) 与 Aβ _1-40/42的共定位淀粉样蛋白斑块中的研究结果支持大脑微生物可能是原因，引发慢性神经炎症，导致阿尔茨海默病 (AD) 的假设。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雄性 Wistar 大鼠单次 LPS 注射（20 微克或 80 微克）的部位，以避免对前脑结构造成机械损伤，同时在整个大脑中引起广泛的炎症。LPS 诱导的慢性神经炎症导致抑郁样行为和空间学习障碍；然而，在注射 LPS 后的 10 个月内，没有证据表明病理特征（例如，tau 的磷酸化）的发展。在用低剂量或高剂量 LPS 治疗的大鼠的海马中观察到通过 CYP46A1 加速胆固醇代谢和通过 HMGCR 抑制胆固醇合成。SH-SY5Y 细胞胆固醇代谢 (CYP46A1) 和 U251 细胞合成 (HMGCR) 的限速酶被炎症刺激物改变，包括 LPS、IL-1β 和 TNF-α，通过 TLR4/MyD88/NF- κB 信号通路。数据表明，将 LPS 注入第三脑室引起的慢性神经炎症可能会诱发抑郁样症状，而胆固醇的减少可能是慢性神经炎症的生物标志物。在我们的模型中缺乏 AD 的病理特征表明革兰氏阴性细菌感染可能不是 AD 的单一原因。