LRP1 knockdown aggravates Aß1-42-stimulated microglial and astrocytic neuroinflammatory responses by modulating TLR4/NF-κB/MAPKs signaling pathways.
Exp Cell Res
; 394(2): 112166, 2020 09 15.
Article
em En
| MEDLINE
| ID: mdl-32645395
ABSTRACT
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 ß-amyloid protein (Aß)-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 Aß1-42-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-1ß (IL-1ß), 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Astrócitos
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Peptídeos beta-Amiloides
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NF-kappa B
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Microglia
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Sistema de Sinalização das MAP Quinases
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Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade
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Receptor 4 Toll-Like
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Inflamação
Limite:
Animals
Idioma:
En
Revista:
Exp Cell Res
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China