Liu Hong, Zhong Lili, Dai Qiaomei, Zhang Yuwei, Yang Jing
Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, No. 24, Heping Road, 150040, Harbin, Heilongjiang, China.
Department of Pathology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China.
Metab Brain Dis. 2022 Dec;37(8):3033-3046. doi: 10.1007/s11011-022-01045-x. Epub 2022 Aug 19.
Senile plaques composed of β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) composed of intracellular hyper-phosphorylated tau are major causes of cognitive impairment and neuronal damage in Alzheimer disease (AD). Astragalin (AST), a naturally-occurring flavonoid compound, was reported to have neuroprotective effects in the brain, but its effects in AD remain unknown. Herein, the learning and memory deficits were alleviated and neuronal damage in the hippocampus were inhibited after the senescence-accelerated mouse prone 8 (SAMP8) mouse were given AST (5 mg/kg or 10 mg/kg) daily by gavage for 2 months. Furthermore, AST reduced Aβ and Aβ deposition, decreased β-carboxyl-terminal fragment (β-CTF) protein level and tau hyper-phosphorylation, but increased α-CTF protein level and glycogen synthase kinase-3beta (GSK-3β) phosphorylation in hippocampus of SAMP8 mice. Meanwhile, the effects of AST on AD were also explored in vitro by treating primary neurons with amyloid-β1-42 oligomers (AβO). Consistently, AST also alleviated amyloid-β1-42 oligomers (AβO)-induced neuronal damage, amyloid plaques, and tau phosphorylation in vitro model. Of note, estrogen receptor (ER)α and ERβ expression in the hippocampus of SAMP8 mice and AβO-treated neurons was significantly decreased but their levels were increased by AST. Moreover, in vivo and in vitro experiments revealed that ER antagonist, Fulvestrant, reversed the effects caused by AST. Altogether, our investigation indicates that AST may ameliorate cognitive deficits and AD-type pathologies in SAMP8 mice and AβO-treated neurons through upregulating ERα and ERβ expression. Our findings indicate the value of AST as a potential reagent for AD treatment.
由β-淀粉样蛋白（Aβ）组成的老年斑和由细胞内过度磷酸化的tau蛋白组成的神经原纤维缠结（NFTs）是阿尔茨海默病（AD）认知障碍和神经元损伤的主要原因。黄芪苷（AST）是一种天然存在的黄酮类化合物，据报道对大脑具有神经保护作用，但其在AD中的作用尚不清楚。在此，衰老加速小鼠8（SAMP8）小鼠每天经口灌胃给予AST（5mg/kg或10mg/kg），持续2个月后，其学习和记忆缺陷得到缓解，海马区的神经元损伤受到抑制。此外，AST减少了Aβ和Aβ沉积，降低了β-羧基末端片段（β-CTF）蛋白水平和tau蛋白过度磷酸化，但增加了SAMP8小鼠海马区的α-CTF蛋白水平和糖原合酶激酶-3β（GSK-3β）磷酸化。同时，通过用淀粉样β1-42寡聚体（AβO）处理原代神经元，在体外探索了AST对AD的影响。一致的是，AST在体外模型中也减轻了淀粉样β1-42寡聚体（AβO）诱导的神经元损伤、淀粉样斑块和tau蛋白磷酸化。值得注意的是，SAMP8小鼠海马区和AβO处理的神经元中雌激素受体（ER）α和ERβ的表达显著降低，但AST可使其水平升高。此外，体内和体外实验表明，ER拮抗剂氟维司群可逆转AST引起的作用。总之，我们的研究表明，AST可能通过上调ERα和ERβ的表达来改善SAMP8小鼠和AβO处理的神经元中的认知缺陷和AD型病理变化。我们的研究结果表明了AST作为AD治疗潜在试剂的价值。
