Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.
Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.
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Fangchinoline通过增强自噬和减轻阿尔茨海默病模型中的氧化应激来减轻认知障碍。
DOI：
10.3389/fcell.2023.1288506
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发表时间：
2023
影响因子：
5.5
通讯作者：
Du, Yehong
中科院分区：
文献类型：
--
作者：
Yi, Lilin;Luo, Man;Wang, Maoju;Dong, Zhifang;Du, Yehong
前言：阿尔茨海默病(AD)是一种衰弱的、进行性的神经退行性疾病，其特征是淀粉样蛋白(Aβ，Aβ)多肽的沉积和随后的氧化应激，导致一连串的细胞毒效应。防己甲素(Fangchinoline，Fan)是从中草药防己中分离得到的一种双苄基异喹啉生物碱，具有抗炎、抗氧化等多种生物活性。然而，FAN对AD的潜在神经保护作用尚不清楚。方法：以稳定转染人瑞典突变体APP695的小鼠神经母细胞瘤N2AAPP细胞作为AD模型。WT小鼠侧脑室注射Aβ1-42多肽建立AD模型。采用免疫印迹分析、免疫沉淀法和行为学评价相结合的方法，观察范丹对AD大鼠的神经保护作用。结果和讨论：研究发现，Fan通过增强自噬并随后促进N2AAPP细胞中BACE1的溶酶体降解，有效地减弱了APP的淀粉样变性过程，表现为P62水平的降低，同时Beclin-1和Lc3-II水平的上升。更重要的是，Fan通过诱导自噬和抑制氧化应激而显著改善Aβ1-42诱导的AD模型小鼠的认知功能障碍，其证据是抗氧化剂包括谷胱甘肽还原酶(GR)、总抗氧化能力(T-AoC)、核因子红系相关因子2(NRF2)、血红素加氧酶-1(HO-1)和超氧化物歧化酶-1(SOD1)的增加，以及促氧化物质包括过氧化氢(H2O2)和诱导型一氧化氮合酶(I-NOS)的减少，同时细胞凋亡标记物裂解caspase-3的减少。综上所述，我们的研究表明，Fan通过促进自噬和减轻氧化应激来改善认知功能障碍，使其成为一种潜在的AD治疗剂。
Introduction: Alzheimer’s disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-β (Aβ) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown. Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aβ1–42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments. Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aβ1–42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD.
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影响因子：
--
作者：
Fan, Bo;Zhang, Xiaoyu;Zhang, Aili
通讯作者：
Zhang, Aili
影响因子：
4.8
作者：
Funmilayo, Eniola;Yeates, Aduke;Tesco, Giuseppina
通讯作者：
Tesco, Giuseppina
影响因子：
56.9
作者：
GOLDE, TE;ESTUS, S;YOUNKIN, SG
通讯作者：
YOUNKIN, SG
影响因子：
4.8
作者：
Kang, Eugene L.;Biscaro, Barbara;Tesco, Giuseppina
通讯作者：
Tesco, Giuseppina
影响因子：
4.8
作者：
Kang, Eugene L.;Cameron, Andrew N.;Tesco, Giuseppina
通讯作者：
Tesco, Giuseppina