Distinct ginseng extracts produce disparate effects on proteostatic support through the autophagy-lysosomal pathway that is linked to synaptic resilience and cognitive health.

The growing incidence of age-related proteinopathies like Alzheimer's disease (AD) warrants high-level understanding of protein quality control pathways and their regulatory factors that influence protein clearance (Farizatto et al. 2017 PLoS ONE 12:e0182895; Boland et al. 2018 Nat Rev Drug Discov 17:660). Alterations to proteostasis mechanisms occur with age leading to the associated gradual disruption of synaptic integrity, the best correlate of cognitive decline during aging and dementia. Poor nutrition is believed to contribute to cognitive aging and many reports suggest natural products, including different types of ginsengs, promote cognitive health. Thus, this study assessed two plant extracts for their ability to amplify a protein clearing enzyme of the autophagy-lysosomal pathway. Note, we focused on American ginseng (P. quinquefolius) and Asian ginseng (P. ginseng) since ginseng root has a long history as a traditional medicine for many diseases and was recently associated with anti-brain aging effects by protecting neurons against oxidative stress, inflammation and stimulating autophagy (Ong et al. 2015 Front Aging Neurosci 16;7:129; Choi et al. 2021 Integr Med Res 10:100450). Long-term hippocampal explants with native circuitries and synaptic density were treated daily with the specific extracts for 3 days. Asian ginseng caused a 50% increase while American ginseng caused a 250-350% increase in the active form of cathepsin B (CatB), a lysosomal protease found to improve clearance of pathogenic proteins and preserve synaptic and cognitive measures in models of proteinopathy (Mueller-Steiner et al. 2006 - Neuron 51:703; Butler et al. 2011 - PLoS ONE 6:e20501; Hwang et al. 2019 - Inter J Mol Sci 20:4432). Of the two treatments, only American ginseng produced a significant correlation between improved levels of the CatB active form and the postsynaptic protein GluA1, and corresponding protection was evident towards both pre- and postsynaptic markers. The LC3I to LC3II conversion was also enhanced in the American ginseng-treated explants, and such was confirmed to occur in the presence of the lysosomal inhibitor chloroquine, thus indicating activation of autophagic flux. Chemical assessment of the two ginsengs by UPLC-Q-ToF-MS suggests the extracts have different profiles of ginsenosides and other molecules, differences that may explain their distinct effects on the hippocampal tissue. The extract-treated hippocampal slice cultures were also subjected to chloroquine infusion that results in a synaptopathogenic cascade. However, American ginseng treatment prevented the synaptic decline due to chloroquine-mediated protein accumulation stress. These findings indicate that ginseng type and/or extraction method are critical for the ability of ginseng extracts to improve protein quality control in the hippocampus, a critical issue as disrupted hippocampal performance underlies the cognitive impairment of several neurodegenerative disorders. The protective influence by a specific natural product points to the protein clearance capacity of neurons as having a mechanistic role for healthy cognitive aging.