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 (A?)-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 A?-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 A? 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 A? 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-?B (NF-?B) signaling pathway and the production of pro-inflammatory cytokines (TNF-?, IL-6, and IL-1?) 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-?B signaling pathway in vivo and in vitro. Thus, tan IIA might be a promising therapeutic drug for halting and preventing AD progression.
