Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro
Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro
复制标题
Santacruzamate A 通过在体内和体外调节 KDELR 和 Mia40-ALR 的功能来增强 ER 应激耐受性，从而改善 AD 样病理学
DOI：
10.3389/fncel.2019.00061
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发表时间：
2019-03-04
影响因子：
5.3
通讯作者：
Li, Wei-ping
中科院分区：
文献类型：
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作者：
Chen, Lei;Liu, Yue-cheng;Li, Wei-ping
聚集的淀粉样β蛋白（A β）和A β诱导的神经元凋亡已被认为是阿尔茨海默病（AD）病理生理学中的关键因素。某些临床前研究结果表明，AD影响的神经元中蛋白聚集体的积累增加激活了未折叠蛋白反应（UPR），这是一种病理现象，主要介导神经元细胞中异常内质网（ER）应激和凋亡级联反应。在本研究中，我们证实了Santacruzamate A（STA，从巴拿马海洋蓝藻中分离的天然产物）减弱A β蛋白片段25-35（A β（25-35））诱导的PC 12细胞毒性，并通过增强ER应激耐受性来挽救APPswe/PS1 dE 9小鼠的认知缺陷。我们首先通过评估caspase-3活性、膜联蛋白V/碘化丙啶（PI）染色和末端脱氧核苷酸转移酶dUTP缺口末端标记染色证明了STA的抗凋亡作用。STA处理的APPswe/PS1 dE 9小鼠的行为测试表明，显着的记忆障碍得到改善，巩固的记忆在2周内稳定维持。机理研究提供了证据，STA通过调节ER滞留信号（KDEL）受体来抑制A β（25-35）诱导的UPR和ER应激，所述ER滞留信号（KDEL）受体增强了ER腔中驻留分子伴侣的滞留。此外，STA调节线粒体膜间空间组装蛋白40（Mia 40）和肝再生增强因子（ALR）的表达，最终减弱线粒体分裂和凋亡途径。总之，我们目前的研究结果表明，KDEL受体和Mia 40-ALR在减轻A β（25-35）诱导的神经毒性中发挥作用，这可能反过来积极调节学习和记忆。这些观察结果支持STA可能是逆转AD进展的有希望的药剂。
Aggregated amyloid-beta protein (A beta) and A beta-induced neuronal apoptosis have been implicated as critical factors in the pathophysiology of Alzheimer's disease (AD). Certain preclinical results have indicated that the increased accumulation of protein aggregates in AD-affected neurons activates the unfolded protein response (UPR), a pathological phenomenon, which predominantly mediates the aberrant endoplasmic reticulum (ER) stress and apoptotic cascades in neuronal cells. In the present study, we confirmed that Santacruzamate A (STA, a natural product isolated from a Panamanian marine cyanobacterium) attenuates A beta protein fragment 25-35 (A beta(25-35))-induced toxicity in PC12 cells and rescues cognitive deficits in APPswe/PS1dE9 mice by enhancing ER stress tolerance. We first demonstrated the anti-apoptotic effects of STA by evaluating caspase-3 activity, annexin V/propidium iodide (PI) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Behavioral testing of STA-treated APPswe/PS1dE9 mice showed that the pronounced memory impairments were ameliorated and that the consolidated memories were stably maintained over a 2-week period. The mechanistic studies provided evidence that STA inhibited A beta(25-35) induced UPR and ER stress by regulating the ER retention signal (KDEL) receptor, which reinforced the retention of resident chaperones in the ER lumen. Furthermore, STA regulated the expression of the mitochondrial intermembrane space assembly protein 40 (Mia40) and augmenter of liver regeneration (ALR), which ultimately attenuated the mitochondrial fission and apoptosis pathways. Together, our present findings suggest that the KDEL receptor and Mia40-ALR play a role in mitigating A beta(25-35)-induced neurotoxicity, which might in turn positively regulate learning and memory. These observations support that STA may be a promising agent for reversing the progression of AD.