Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.
Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.
Mol Cell Neurosci. 2018 Dec;93:1-9. doi: 10.1016/j.mcn.2018.09.002. Epub 2018 Sep 22.
Centella asiatica is a medicinal plant used to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates β-amyloid (Aβ)-induced spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its in vivo mechanism of improving Aβ-related cognitive impairment. This study investigates the effects of CAW on learning, memory and executive function as well as mitochondrial function and antioxidant response in the 5xFAD model of Aβ accumulation. Seven month old 5xFAD female mice were treated with CAW (2 mg/mL) in their drinking water for two weeks prior to behavioral testing. Learning, memory and executive function were assessed using the object location memory task (OLM), conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) test. Mitochondrial function was profiled using the Seahorse XF platform in hippocampal mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial, antioxidant and synaptic proteins. CAW improved performance in all behavioral tests in the 5xFAD but had no effect on WT animals. Hippocampal mitochondrial function was improved and hippocampal and cortical expression of mitochondrial genes was increased in CAW-treated 5xFAD mice. Gene expression of the transcription factor NRF2, as well as its antioxidant target enzymes, was also increased with CAW treatment in both WT and 5xFAD mice. CAW treatment also decreased Aβ-plaque burden in the hippocampus of treated 5xFAD mice but had no effect on plaques in the cortex. These data show that CAW can improve many facets of Aβ-related cognitive impairment in 5xFAD mice. Oral treatment with CAW also attenuates hippocampal mitochondrial dysfunction in these animals. Because mitochondrial dysfunction and oxidative stress accompany cognitive impairment in many pathological conditions beyond Alzheimer's disease, this suggests potentially broad therapeutic utility of CAW.
积雪草是一种药用植物，用于增强记忆力。我们之前的研究表明，积雪草的水提取物（CAW）可减轻小鼠β-淀粉样蛋白（Aβ）诱导的空间记忆缺陷，并改善神经元健康。然而，CAW 对其他认知领域的影响以及其改善与 Aβ 相关认知障碍的体内机制仍未得到探索。本研究调查了 CAW 对学习、记忆和执行功能以及线粒体功能和抗氧化反应的影响，这些影响与 5xFAD 模型中的 Aβ 积累有关。7 月龄的 5xFAD 雌性小鼠在行为测试前两周通过饮用水接受 CAW（2mg/mL）治疗。使用物体位置记忆任务（OLM）、条件性恐惧反应（CFR）和气味辨别反转学习（ODRL）测试评估学习、记忆和执行功能。使用 Seahorse XF 平台在这些动物的海马线粒体中对线粒体功能进行分析，并从这些动物中采集组织以评估线粒体、抗氧化和突触蛋白。CAW 改善了 5xFAD 小鼠所有行为测试的表现，但对 WT 动物没有影响。CAW 处理改善了 CAW 处理的 5xFAD 小鼠的海马线粒体功能，并增加了 CAW 处理的 5xFAD 小鼠的海马和皮质中线粒体基因的表达。CAW 处理还增加了 WT 和 5xFAD 小鼠中的转录因子 NRF2 的基因表达及其抗氧化靶酶。CAW 处理还减少了治疗的 5xFAD 小鼠海马中的 Aβ 斑块负担，但对皮质中的斑块没有影响。这些数据表明，CAW 可以改善 5xFAD 小鼠与 Aβ 相关的认知障碍的许多方面。口服 CAW 治疗还减轻了这些动物的海马线粒体功能障碍。由于线粒体功能障碍和氧化应激伴随着阿尔茨海默病以外的许多病理状况下的认知障碍，这表明 CAW 具有潜在的广泛治疗用途。
