Neuroinflammation is an important pathological feature and an early event in the pathogenesis of Alzheimer's disease (AD), which is characterized by activation of microglia and astrocytes. Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic receptor that is abundantly expressed in neurons, microglia, and astrocytes, and plays a critical role in AD pathogenesis. There is increasing evidence to show that LRP1 regulates inflammatory responses by modulating the release of pro-inflammatory cytokines and phagocytosis. However, the effects of LRP1 on β-amyloid protein (Aβ)-induced microglial and astrocytic neuroinflammatory responses and its underlying mechanisms have not been studied in detail. In the present study, knockdown of LRP1 significantly enhanced Aβ_1–42-stimulated neuroinflammation by increasing the production of pro-inflammatory cytokines in both BV2 microglial cells and mouse primary astrocytes. Furthermore, it is revealed that LRP1 knockdown further led to the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. The phosphorylation of IκBα, p38, and JNK was significantly up-regulated in LRP1 knockdown BV2 microglial cells and primary astrocytes. Meanwhile, LRP1 knockdown increased expression of the NF-κB p65 subunit in the nucleus while decreased its expression in the cytoplasm. Besides, the upstream signaling adaptor molecules such as toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), and tumor necrosis factor receptor-associated factor 6 (TRAF6) were also further increased. Moreover, blockade of NF-κB, p38, and JNK inhibited the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by the knockdown of LRP1. Taken together, these findings indicated that LRP1 as an effective therapeutic target against AD and other neuroinflammation related diseases.

神经炎症是阿尔茨海默氏病（AD）发病机理中的重要病理特征和早期事件，其特征在于小胶质细胞和星形胶质细胞的活化。低密度脂蛋白受体相关蛋白1（LRP1）是一种内吞受体，在神经元，小胶质细胞和星形胶质细胞中大量表达，并且在AD发病机理中起关键作用。越来越多的证据表明LRP1通过调节促炎性细胞因子的释放和吞噬作用来调节炎症反应。然而，尚未详细研究LRP1对β淀粉样蛋白（Aβ）诱导的小胶质细胞和星形胶质细胞神经炎症反应的影响及其潜在机制。在本研究中，敲低LRP1可显着增强_Aβ1–42通过增加BV2小胶质细胞和小鼠原代星形胶质细胞中促炎性细胞因子的产生来刺激神经炎症。此外，已揭示LRP1敲低进一步导致核因子-κB（NF-κB）和有丝分裂原激活的蛋白激酶（MAPKs）信号通路的激活。在LRP1抑制的BV2小胶质细胞和原代星形胶质细胞中，IκBα，p38和JNK的磷酸化显着上调。同时，LRP1敲低增加了核中NF-κBp65亚基的表达，同时降低了其在细胞质中的表达。此外，上游信号转导分子，如toll样受体4（TLR4），髓样分化初级反应蛋白88（MyD88）和肿瘤坏死因子受体相关因子6（TRAF6）也进一步增加。此外，阻断NF-κB，p38和JNK可抑制LRP1敲低诱导的肿瘤坏死因子-α（TNF-α），白介素-1β（IL-1β）和白介素-6（IL-6）的产生。综上所述，这些发现表明LRP1是针对AD和其他神经炎症相关疾病的有效治疗靶标。