Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models

作者全名："Yi, Lilin; Luo, Man; Wang, Maoju; Dong, Zhifang; Du, Yehong"

作者地址："[Yi, Lilin; Luo, Man; Wang, Maoju; Dong, Zhifang; Du, Yehong] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Pediat Res Inst,Childrens Hosp,Minist Educ,Chongqi, Chongqing, Peoples R China; [Dong, Zhifang] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing, Peoples R China"

通信作者："Dong, ZF; Du, YH (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Pediat Res Inst,Childrens Hosp,Minist Educ,Chongqi, Chongqing, Peoples R China.; Dong, ZF (通讯作者)，Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing, Peoples R China."

来源：FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001129946400001

JCR分区：Q1

影响因子：4.6

年份：2023

卷号：11

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：alzheimer's disease; amyloid-beta; BACE1; autophagy; oxidative stress; cognition

摘要："Introduction: Alzheimer's disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-beta (A beta) 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: N2A(APP) 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 A beta(1-42) 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 N2A(APP) 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 A beta(1-42)-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."

基金机构："National Natural Science Foundation of China [32371030, 82371194, 82071395, 82001158]; Natural Science Foundation of Chongqing [2022NSCQ-LZX0010, cstc2021ycjh-bgzxm0186]; CQMU Program for Youth Innovation in Future Medicine [W0044]"

基金资助正文："The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (32371030, 82371194, 82071395, and 82001158), the Natural Science Foundation of Chongqing (2022NSCQ-LZX0010 and cstc2021ycjh-bgzxm0186) and CQMU Program for Youth Innovation in Future Medicine (W0044)."