Abstract
Attenuating β amyloid- (Aβ-) induced microglial activation is considered to be effective in treating Alzheimer's disease (AD). Berberine (BBR) can reduce microglial activation in Aβ-treated microglial cells; the mechanism, however, is still illusive. Silencing of cytokine signaling factor 1 (SOCS1) is the primary regulator of many cytokines involved in immune reactions, whose upregulation can reverse the activation of microglial cells. Microglia could be activated into two different statuses, classic activated state (M1 state) and alternative activated state (M2 state), and M1 state is harmful, but M2 is beneficial. In the present study, N9 microglial cells were exposed to Aβ to imitate microglial activation in AD. And Western blot and immunocytochemistry were taken to observe inducible nitric oxide synthase (iNOS), Arginase-1 (Arg-1), and SOCS1 expressions, and the enzyme-linked immunosorbent assay (ELISA) was used to measure inflammatory and neurotrophic factor release. Compared with the normal cultured control cells, Aβ exposure markedly increased the level of microglial M1 state markers (P < 0.05), including iNOS protein expression, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 releases, and BBR administration upregulated SOSC1 expression and the level of microglial M2 state markers (P < 0.05), such as Arg-1 expression, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF) releases, downregulating the SOCS1 expression by using siRNA, however, significantly reversed the BBR-induced effects on microglial M1 and M2 state markers and SOCS1 expression (P < 0.05). These findings indicated that BBR can inhibit Aβ-induced microglial activation via modulating the microglial M1/M2 activated state, and SOCS1 mediates the process.
Highlights
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, characterized as progressive memory and cognitive dysfunctions, leading to great economic and social burden to the family with AD patients [1,2,3]
As the microglial cells of M1 state can secrete proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6, the M1 state is believed to be harmful to the brain; in contrast, the microglia of M2 state can release anti-inflammatory and neurotrophic factors, such as IL-10, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), which is considered to be beneficial [13]
To explore a suitable dose of BBR, in this experiment, the N9 microglia were divided into the control group, Aβ exposure group, 0.1 μM BBR+5 μM Aβ group, 1 μM BBR+5 μM Aβ group, and 5 μM BBR+5 μM Aβ group; after incubation for 24 h, we took the Western blot analysis to assess inducible nitric oxide synthase (iNOS) and Silencing of cytokine signaling factor 1 (SOCS1) expression levels, and the TNF-α concentration in the medium was measured by using the enzyme-linked immunosorbent assay (ELISA) (Figures 2(a) and 2(b))
Summary
Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, characterized as progressive memory and cognitive dysfunctions, leading to great economic and social burden to the family with AD patients [1,2,3]. Searching for effective methods or therapy for AD is very urgent. A high level of Aβ in the brain can activate microglial cells and induce neuroinflammation [6, 7]. Chronic inflammation in brain tissue can result in neuronal injury and even death [8, 9]. For this reason, alleviating Aβinduced microglial activation is regarded as an effective therapy for AD. Silencing of cytokine signaling factor 1 (SOCS1) is the primary regulator of many cytokines, mainly expressed in immunocytes, including macrophages in the peripheral tissue and microglial cells of the central nervous system (CNS).
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