地黄饮子调节PERK/elF2通路抑制能量代谢障碍AD小鼠脑内淀粉样蛋白累积的作用机制

张志辰; 温彬宇; 高俊峰; 唐旭; 黄倩倩; 马涛

doi:10.13422/j.cnki.syfjx.20182136

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地黄饮子调节PERK/elF2通路抑制能量代谢障碍AD小鼠脑内淀粉样蛋白累积的作用机制

地黄饮子治疗阿尔茨海默病的实验研究专题 | 更新时间：2024-09-23

- 地黄饮子调节PERK/elF2通路抑制能量代谢障碍AD小鼠脑内淀粉样蛋白累积的作用机制
- Effect and Mechanism of Dihuang Yinzi on Cerebral -Amyloid Accumulation by Depressing PERK/eIF2 Pathway in Energy Inhibited AD Mice
- 中国实验方剂学杂志 2018年24卷第21期页码：91-98
- 作者机构：
- 作者简介：
- 基金信息：
  
  国家自然科学基金项目（81673929）
- DOI：10.13422/j.cnki.syfjx.20182136
  中图分类号： R285.5
- 纸质出版日期：2018
- 稿件说明：
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张志辰, 温彬宇, 高俊峰, 等. 地黄饮子调节PERK/elF2通路抑制能量代谢障碍AD小鼠脑内淀粉样蛋白累积的作用机制[J]. 中国实验方剂学杂志, 2018,24(21):91-98.

ZHANG Zhi-chen, WEN Bin-yu, GAO Jun-feng, et al. Effect and Mechanism of Dihuang Yinzi on Cerebral -Amyloid Accumulation by Depressing PERK/eIF2 Pathway in Energy Inhibited AD Mice[J]. Chinese journal of experimental traditional medical formulae, 2018, 24(21): 91-98.
张志辰, 温彬宇, 高俊峰, 等. 地黄饮子调节PERK/elF2通路抑制能量代谢障碍AD小鼠脑内淀粉样蛋白累积的作用机制[J]. 中国实验方剂学杂志, 2018,24(21):91-98. DOI： 10.13422/j.cnki.syfjx.20182136.

ZHANG Zhi-chen, WEN Bin-yu, GAO Jun-feng, et al. Effect and Mechanism of Dihuang Yinzi on Cerebral -Amyloid Accumulation by Depressing PERK/eIF2 Pathway in Energy Inhibited AD Mice[J]. Chinese journal of experimental traditional medical formulae, 2018, 24(21): 91-98. DOI： 10.13422/j.cnki.syfjx.20182136.

摘要

目的：以能量代谢障碍淀粉样前体蛋白（APP）/早老素基因1（PS1）转基因小鼠为阿尔茨海默病（Alzheimer's disease， AD）模型，探讨地黄饮子通过调控蛋白激酶R样内质网激酶（protein kinase r-like endoplasmic reticulum kinase，PERK），真核细胞起始因子2α（eukaryotic initiation factor 2α， eIF2α）通路抑制内质网应激导致的β-淀粉样蛋白（Aβ）累积的作用机制。方法：4月龄 APP/PS1转基因小鼠随机分为正常组、模型组、阳性药（安理申）组、地黄饮子低、中、高剂量组。除正常组小鼠腹腔注射无菌生理盐水外，其余各组小鼠均腹腔注射100 mg·kg-1 3-硝基丙酸（3-nitropropionic acid， 3-NP）1次。小鼠造模后，立即给药。灌胃给药1周后，Morris水迷宫实验检测小鼠学习记忆能力，高效液相色谱法检测小鼠脑内三磷酸腺苷（ATP），二磷酸腺苷（ADP），一磷酸腺苷（AMP）含量，并计算脑能荷（energy charge， EC）。蛋白免疫印迹法（Western blot）检测小鼠脑内PERK，eIF2α磷酸化水平，β-淀粉样前体蛋白水解酶1（BACE1）表达水平。实时荧光定量聚合酶链式反应（Real-time PCR）检测BACE1 mRNA表达水平。酶联免疫吸附测定法（ELISA）检测小鼠脑内Aβ含量。结果：与正常组比较，Morris水迷宫实验结果显示，在定位巡航实验中，地黄饮子可以明显缩短模型小鼠的逃避潜伏期（P<0.05，P<0.01）；空间探索实验中，地黄饮子可以增加模型小鼠穿越目标区域的次数（P<0.05，P<0.01）和在目标象限的停留时间（P<0.01），减少相对象限的停留时间（P<0.05，P<0.01）。地黄饮子可以显著降低AMP水平，明显升高ATP，ADP水平，显著提高模型小鼠脑内EC水平（P<0.05，P<0.01），抑制PERK，eIF2α的磷酸化（P<0.01）和BACE1的蛋白水平（P<0.01），但对BACE1 mRNA转录没有显著影响。地黄饮子能够减少模型小鼠脑内Aβ的含量（P<0.01）。结论：地黄饮子可以通过阻止能量代谢障碍导致的内质网应激通路PERK/eIF2α激活，抑制BACE1的翻译，从而减少能量代谢障碍APP/PS1小鼠脑内Aβ的累积。

Abstract

Objective: To explore the effect and mechanism of Dihuang Yinzi on β-amyloid protein (Aβ) accumulation via protein kinase r-like endoplasmic reticulum kinase (PERK)

eukaryotic initiation factor 2α (eIF2α) pathway in energy inhibited APP/PS1 transgenic Alzheimer's disease (AD) mice. Method: APP/PS1 transgenic mice at 4-month-old were randomly divided into normal control group

model group

positive drug group (Aricept)

Dihuang Yinzi low-

medium-and high-dose groups. Mice were intraperitoneally injected with 100 mg·kg-1 3-nitropropionic acid (3-NP) except those in normal control group (intraperitoneally injected with normal saline) to establish models. Drug administration was given immediately modeling

and after 1 week of intragastric administration

the learning and memory ability of mice was tested by Morris water maze test; the contents of adenosine triphosphate (ATP)

adenosine diphosphate (ADP)

and adenosine monophosphate (AMP) in the brain of mice were detected by high performance liquid chromatography (HPLC); and the energy charge (EC) was calculated.Western blot was performed to detect the levels of PERK

eIF2α phosphorylation and β-amyloid precursor protein hydrolase 1 (BACE1) expression in the brain of mice. The transcriptional level of BACE1 gene was detected by Real-time fluorescence quantitative polymerase chain reaction(PCR). The content of cerebral Aβ was detected by enzyme-linked immunosorbent assay (ELISA). Result: Morris water maze test showed that as compared with the normal group

Dihuang Yinzi can significantly shorten the escape latency of model mice in navigation test (P<0.05

P<0.01). In spatial probe test

Dihuang Yinzi can increase the number passing the target area (P<0.05

P<0.01) and the residence time in target quadrant (P<0.01)

reduce the residence time in opposite quadrant (P<0.05

P<0.01). Dihuang Yinzi can significantly decrease AMP level

increase ATP and ADP levels

and significantly improve the cerebral EC level (P<0.05

P<0.01)

inhibit the phosphorylation of PERK and eIF2α (P<0.01)

decrease the protein level of BACE1 (P<0.01)

but had no significant effect on BACE1 gene transcription. Besides

Dihuang Yinzi can reduce the cerebral Aβ content in model mice (P<0.01). Conclusion: Dihuang Yinzi could prevent energy metabolism disturbance-induced endoplasmic reticulum stress via inhibiting PERK/eIF2α activation

reduce cerebral Aβ accumulation

and improve cognition in 3-NP induced energy inhibited APP/PS1 mice.

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