Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in β-amyloid overexpressing mice

Abstract

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 5×FAD model of Aβ accumulation. Seven month old 5×FAD female mice were treated with CAW (2mg/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 5×FAD 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 5×FAD 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 5×FAD mice. CAW treatment also decreased Aβ-plaque burden in the hippocampus of treated 5×FAD 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 5×FAD 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.

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

“…For instance, Hong et al (2013) used proteomic analysis to demonstrate activation of the NRF2 transcriptional pathway in 5XFAD mice at four months of age [100], which is consistent with ARE activation in Alzheimer's patients [101]. Our laboratory has shown Nrf2 expression, specifically, is elevated further with CAW treatment in seven month old 5XFAD female mice [33], an observation shown in the present study to occur in a CAW dose-dependent manner. This suggests CAW improves antioxidant signaling to combat the ever increasing oxidative stress mediated by the expanding Aβ pathology indicative of AD.…”

“…We have confirmed that these mechanisms also operate in aging wild-type (WT) mice [1]. In this study, we expand on our previous studies in female Tg2576 [13] and female 5XFAD mice [33] treated with 200 mg/kg/d CAW. The present study includes 5XFAD mice and WT littermates of both genders and treatment with a range of CAW doses (0, 200, 500, 1000 mg/kg/d).…”

“…This suggests a mitigating impact on oxidative stress regardless of plaque burden in these animals. However, in our previous experiments, CAW treatment has been seen to reduce Aβ plaques in 5XFAD hippocampus [33] where a higher baseline Aβ burden (> 3%) was present. The impact of CAW on 5XFAD Aβ plaque burden should be resolved in future experiments.…”

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

“…Bar, 25 μm in all images. Quantitation of the cytoplasmic SOD-1 and HO-1 fluorescent signals is shown in Additional file 3: Figure S3 alterations in mitochondrial respiration and ATP production both in neuronal cultures and transgenic mouse models [97][98][99][100][101][102]. In spite of their potential for the development of future therapeutic strategies, the consequences of the prolonged use of Nrf2 activators should be further explored, specially taking into consideration the reported association of Nrf2 exacerbated activation with certain types of cancer [103].…”

Intermittent hypoxia improves cognition and reduces anxiety‐related behavior in APP/PS1 mice

“…Pathological deposition of Aβ in the brain is a well‐known characteristic of AD (Armstrong, ). Aβ production is associated with impaired hippocampal synaptic plasticity, which leads to behavioral abnormalities (Gray et al, ). In the current study, we observed that IH exposure significantly reduced the number of Aβ plaques in the hippocampus of AD mice.…”