小檗碱通过调节 β-淀粉样蛋白产生和内质网应激改善阿尔茨海默病小鼠模型的行为和认知缺陷,ACS Chemical Neuroscience

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小檗碱通过调节 β-淀粉样蛋白产生和内质网应激改善阿尔茨海默病小鼠模型的行为和认知缺陷
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2021-05-13 , DOI: 10.1021/acschemneuro.0c00808
Yubin Liang ₁ , Chenghui Ye ₂ , Yuling Chen ₃ , Ying Chen ₂ , Shiyuan Diao ₂ , Min Huang ₂

Affiliation

阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征在于β -淀粉样蛋白 (Aβ)、神经原纤维缠结和神经元细胞死亡。积极的 Aβ 积累加速老年斑形成并扰乱内质网 (ER) 功能。Aβ 积累诱导的变化会刺激未折叠蛋白反应 (UPR)，从而引发神经元凋亡。蛋白激酶 RNA 样内质网激酶 (PERK) 的激活依赖于压力，可增加真核翻译起始因子-2α (eIF2α) 的磷酸化。eIF2α 促进 β 位点 APP 裂解酶 1 (BACE1) 的合成，进而促进 Aβ 的生成和随后的神经元凋亡。在这项研究中，我们研究了小檗碱是否可以改善阿尔茨海默病 (3 × Tg AD) 小鼠三重转基因小鼠模型的认知缺陷。我们的结果表明，小檗碱治疗可能会抑制 PERK/eIF2α 信号介导的 BACE1 翻译，从而减少 Aβ 的产生和由此导致的神经元凋亡。此外，小檗碱可能具有神经保护作用，通过减弱内质网应激和氧化应激。总之，我们的研究证明了小檗碱治疗 AD 的潜力。

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Berberine Improves Behavioral and Cognitive Deficits in a Mouse Model of Alzheimer’s Disease via Regulation of β-Amyloid Production and Endoplasmic Reticulum Stress

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by β-amyloid (Aβ), neurofibrillary tangles, and neuronal cell death. Aggressive Aβ accumulation accelerates senile plaque formation and perturbs endoplasmic reticulum (ER) function. Aβ accumulation-induced changes stimulate the unfolded protein response (UPR), which can trigger neuronal apoptosis. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), whose activation is stress-dependent, increases the phosphorylation of eukaryotic translation initiation factor-2α (eIF2α). eIF2α promotes the synthesis of β-site APP cleavage enzyme 1 (BACE1), which in turn facilitates Aβ generation and subsequent neuronal apoptosis. In this study, we investigated whether berberine could improve cognitive deficits in the triple-transgenic mouse model of Alzheimer’s disease (3 × Tg AD) mice. Our results revealed that berberine treatment may inhibit PERK/eIF2α signaling-mediated BACE1 translation, thus reducing Aβ production and resultant neuronal apoptosis. Further, berberine may have neuroprotective effects, via attenuation of ER stress and oxidative stress. In sum, our study demonstrates the therapeutic potential of berberine for treating AD.

更新日期：2021-06-02

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