Centella asiatica improves synaptic plasticity and activates antioxidant and mitochondrial pathways in hippocampal neurons from an Alzheimer's disease mouse model

Centella asiatica (L.) Urban (Apiaceae) is a plant traditionally used to enhance cognition. The water extract of C. asiatica (CAW) is a complex mixture of compounds that reverses β-amyloid (Aβ)-induced, as well as age-related, cognitive deficits in mice [1, 2] and elicits antioxidant and mitoprotective effects in vitro [3] and in vivo [2]. Here we explore the effects of CAW on neuronal morphology in the context of Aβ exposure as well as in healthy neurons. We also investigate the mitochondrial and antioxidant effects of CAW in those neurons and we evaluate the effects of individual compounds found in CAW on these endpoints. Hippocampal neurons isolated from Aβ expressing (Tg2576) mice and wildtype (WT) littermates were treated either with CAW or caffeoylquinic acids (CQAs) and triterpenes from the extract and dendritic arborization, synaptic density, mitochondrial and antioxidant gene expression and mitochondrial bioenergetics were evaluated. CAW attenuated Aβ-induced deficits in dendritic arborization and spine density in isolated hippocampal neurons and improved both endpoints in WT neurons as well. DiCQAs from CAW produced similar increases in arborization and spine density in neurons from both genotypes while monoCQAs and triterpenes from the extract had no effect. These same markers of neuronal health were likewise improved by CAW in vivo in both the hippocampus and cortex. CAW also improved mitochondrial function in isolated hippocampal neurons from both genotypes and increased the expression of antioxidant and mitochondrial genes. CAW improved neuronal health and activated antioxidant response and mitochondrial pathways in hippocampal neurons. Studies are underway to determine whether these effects are related and if they contribute to cognitive enhancing properties of CAW in vivo. Additionally work is ongoing to determine which compounds, or combination thereof, contribute to the observed effects of CAW on mitochondrial, antioxidant and cognitive endpoints both in vitro and in vivo.

Acknowledgements: This work was funded by NIH-NCCIH grant R01AT008099 (Soumyanath), NIH-NCCIH grant K99 AT008831 (Gray) and by a Department of Veterans Affairs Merit Review Grant (Quinn).

Keywords: Synaptic plasticity, Centella asiatica, mitochondrial dysfunction, reactive oxygen species, β-amyloid.

References:

[1] Soumyanath A, Zhong YP, Henson E, Wadsworth T, Bishop J, Gold BG, Quinn JF. Centella asiatica extract improves behavioural deficits in a mouse model of Alzheimer's disease: Investigation of a possible mechanism of action. Int J Alzheimers Dis 2012; 381974

[2] Gray NE, Harris CJ, Quinn JF, Soumyanath A. Centella asiatica modulates antioxidant and mitochondrial pathways and improves cognitive function in mice. J Ethnopharmacol 2016; 180: 78 – 86

[3] Gray NE, Sampath H, Zweig JA, Quinn JF, Soumyanath A. Centella asiatica attenuates amyloid-β-induced oxidative stress and mitochondrial dysfunction. J. Alzheimers Dis 2015; 45: 933 – 946