Abstract
BackgroundGlial activation and neuroinflammation play a crucial role in the pathogenesis and development of Alzheimer’s disease (AD). The receptor for advanced glycation end products (RAGE)-mediated signaling pathway is related to amyloid beta (Aβ)-induced neuroinflammation. This study aimed to investigate the neuroprotective effects of tanshinone IIA (tan IIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza Bunge, against Aβ-induced neuroinflammation, cognitive impairment, and neurotoxicity as well as the underlying mechanisms in vivo and in vitro.MethodsOpen-field test, Y-maze test, and Morris water maze test were conducted to assess the cognitive function in APP/PS1 mice. Immunohistochemistry, immunofluorescence, thioflavin S (Th-S) staining, enzyme-linked immunosorbent assay (ELISA), real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and western blotting were performed to explore Aβ deposition, synaptic and neuronal loss, microglial and astrocytic activation, RAGE-dependent signaling, and the production of pro-inflammatory cytokines in APP/PS1 mice and cultured BV2 and U87 cells.ResultsTan IIA treatment prevented spatial learning and memory deficits in APP/PS1 mice. Additionally, tan IIA attenuated Aβ accumulation, synapse-associated proteins (Syn and PSD-95) and neuronal loss, as well as peri-plaque microgliosis and astrocytosis in the cortex and hippocampus of APP/PS1 mice. Furthermore, tan IIA significantly suppressed RAGE/nuclear factor-κB (NF-κB) signaling pathway and the production of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in APP/PS1 mice and cultured BV2 and U87 cells.ConclusionsTaken together, the present results indicated that tan IIA improves cognitive decline and neuroinflammation partly via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro. Thus, tan IIA might be a promising therapeutic drug for halting and preventing AD progression.
Highlights
Glial activation and neuroinflammation play a crucial role in the pathogenesis and development of Alzheimer’s disease (AD)
Antibodies were from several companies: anti-receptor for advanced glycation end products (RAGE) and anti-NeuN were obtained from Abcam (Cambridge, MA, USA); anti-ionized calcium-binding adapter molecule 1(Iba-1) was purchased from GeneTex (Alton Parkway Irvine, CA, USA); anti-phospho-IκBα (Ser32), anti-total-IκBα, antiphospho-nuclear factor-κB (NF-κB) p65 (Ser536), anti-total-NF-κB p65, anti-synaptophysin (Syn), anti-PSD-95, anti-histone H3, and FITC-conjugated goat anti-rabbit IgG were obtained from Cell Signaling Technologies (Beverly, MA, USA); anti-β-actin was purchased from Santa Cruz (CA, USA); anti-MOAB2, anti-glial fibrillary acidic protein (GFAP), and Cy3-conjugated goat anti-mouse IgG were obtained from Novus Biologicals (Littleton, CO, USA); horseradish peroxidase (HRP)-conjugated goat anti-rabbit and goat anti-mouse IgG were purchased from Pierce Corporation (Rockford, IL, USA) and Zhongshan Golden Bridge Biotechnology Corporation (Beijing, China)
In summary, the present study demonstrated that tan Tanshinone IIA (IIA) ameliorated the neuropathologies including synaptic and neuronal loss, gliosis, neuroinflammatory responses, and Amyloid beta (Aβ) deposition, accompanied by an improved spatial cognitive function
Summary
Glial activation and neuroinflammation play a crucial role in the pathogenesis and development of Alzheimer’s disease (AD). The receptor for advanced glycation end products (RAGE)-mediated signaling pathway is related to amyloid beta (Aβ)-induced neuroinflammation. Aβ deposition and chronic neuroinflammatory responses interplay with each other to form a vicious cycle that expands the damaging effects [5] Under inflammatory conditions, both activated microglia and astrocytes can produce and secrete multiple pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), all of which can confer neurotoxicity [6]. RAGE is expressed on neurons, microglia, astrocytes, and endothelial cells [9,10,11]. In astrocytes and cerebral endothelial cells, the activation of RAGE by Aβ induces oxidative stress by increasing the production of reactive oxygen species [12].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
