Bee venom phospholipase A2 ameliorates amyloidogenesis and neuroinflammation through inhibition of signal transducer and activator of transcription-3 pathway in Tg2576 mice

被引:18
作者
Ham, Hyeon Joo [1 ,2 ]
Han, Sang-Bae [1 ,2 ]
Yun, Jaesuk [1 ,2 ]
Yeo, In Jun [1 ,2 ]
Ham, Young Wan [3 ]
Kim, Se Hyun [4 ]
Park, Pil-Hoon [5 ]
Choi, Dong-Young [5 ]
Hong, Jin Tae [1 ,2 ]
机构
[1] Chungbuk Natl Univ, Coll Pharm, Osongsaengmyeong 1 Ro, Cheongju 28160, Chungbuk, South Korea
[2] Chungbuk Natl Univ, Med Res Ctr, Osongsaengmyeong 1 Ro, Cheongju 28160, Chungbuk, South Korea
[3] Utah Valley Univ, Dept Chem, 800 W Univ Pkwy, Orem, UT 84058 USA
[4] INISTst Co LTD, 767 Sinsu Ro, Yongin 16827, Gyeonggi Do, South Korea
[5] Yeungnam Univ, Coll Pharm, 280 Daehak Rd, Gyeonsan 38541, Gyeongbuk, South Korea
基金
新加坡国家研究基金会;
关键词
Bee venom phospholipase A2; Alzheimer's disease; Amyloidogenesis; Neuroinflammation; STAT3; LIPOPOLYSACCHARIDE-INDUCED NEUROINFLAMMATION; ALZHEIMERS-DISEASE; MOUSE MODEL; MEMORY IMPAIRMENT; OXIDATIVE STRESS; BETA-SECRETASE; IN-VITRO; STAT3; MICROGLIA; INFLAMMATION;
D O I
10.1186/s40035-019-0167-7
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Background Neuroinflammation and accumulation of beta-amyloid (A beta) play a significant role in the onset and progression of Alzheimer's disease (AD). Our previous study demonstrated that signal transducer and activator of transcription-3 (STAT3) plays a major role in neuroinflammation and amyloidogenesis. Methods In the present study, we investigated the inhibitory effect of bee venom phospholipase A2 (bvPLA2) on memory deficiency in Tg2576 mice, which demonstrate genetic characteristics of AD and the mechanism of its action at the cellular and animal level. For in vivo study, we examined the effect of bvPLA2 on improving memory by conducting several behavioral tests with the administration of bvPLA2 (1 mg/kg) to Tg2576 mice. For in vitro study, we examined the effect of bvPLA2 on amyloidogenesis and neuroinflammation by treating bvPLA2 on LPS-activated BV2 cells. Results We found that bvPLA2 alleviated memory impairment in Tg2576 mice, as demonstrated in the behavioral tests assessing memory. In the bvPLA2-treated group, A beta, amyloid precursor protein (APP), and beta-secretase 1 (BACE1) levels and beta-secretase activity were significantly decreased. Expression of pro-inflammatory cytokines and inflammation-related proteins decreased in the brain of bvPLA2-treated group, whereas anti-inflammatory cytokines increased. In addition, bvPLA2 reduced STAT3 phosphorylation in the brains of the bvPLA2-treated group. At the cellular level, bvPLA2 inhibits production of nitric oxide, pro-inflammatory cytokines, and inflammation-related proteins including p-STAT3. Additionally, bvPLA2 inhibits the production of A beta in cultured BV-2 cells. Results from the docking experiment, pull-down assay, and the luciferase assay show that bvPLA2 directly binds STAT3 and, thus, regulates gene expression levels. Moreover, when the STAT3 inhibitor and bvPLA2 were administered together, the anti-amyloidogenic and anti-inflammatory effects were further enhanced than when they were administered alone. Conclusion These results suggest that bvPLA2 could restore memory by inhibiting the accumulation of A beta and inflammatory responses via blockage of STAT3 activity.
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页数:16
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