Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro

Abstract

Background 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. 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. Methods Open-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. Results Tan 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. Conclusions Taken 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.

Downregulation of TREM2 Expression Exacerbates Neuroinflammatory Responses Through TLR4-Mediated MAPK Signaling Pathway in a Transgenic Mouse Model of Alzheimer’s Disease

“…The toxic oligomers of Aβ 1−42 were prepared as previously described [6,35]. Brie y, lyophilized Aβ 1−42 peptide was dissolved in HFIP at a concentration of 1 mg/mL, separated into aliquots in sterile microcentrifuge tubes, dried under vacuum, and stored at − 80°C.…”

“…Spontaneous alternation in the Y-maze test, which was used to assess short-term working spatial memory and exploratory activity of mice, was performed as described before [7,35]. The Y-maze apparatus consists of three arms at 120° angles (width 6 cm × length 30 cm × height 15 cm) to each other.…”

“…Spatial learning and reference memory of mice was evaluated by the MWM test as previously described [7,35]. The apparatus consisted of a 120 cm diameter circular plastic pool, lled with opaque water at the depth of 35 cm and controlled temperature of 25 ± 2°C.…”

“…To detect dense-core amyloid plaques, Th-S staining was performed as previously described [35,36]. Brie y, the free-oating sections were washed with phosphate buffered saline (PBS, pH 7.4) three times, and then were brie y rinsed in distilled water.…”

“…Immunohistochemistry staining was carried out as previously described [35,36]. Brie y, free-oating sections were washed with PBS, pre-treated in 3% hydrogen peroxide, and maintained in blocking solution (1% BSA and 0.3% Triton X-100) for 1 h at room temperature.…”