Commonalities of Ginseng Extract (P. quinquefolius) and Exercise Mimetic β-GPA for Reducing Age-related Cognitive Deficits and Modulating the Autophagy-Lysosomal Pathway

Abstract

<b>Abstract ID 23079</b> <b>Poster Board 212</b> Neuronal disturbances signify brain vulnerability that fosters cognitive impairment, whether facilitated by excitatory over-activation, toxin exposures, metabolic distress, trauma-inducing events, or aging. Across such dementia risk factors, negative effects on proteostasis and synaptic integrity gradually increase the risk for mild cognitive impairment (MCI) and the continuum to dementia. Removal of old and damaged proteins by the autophagy-lysosomal pathway clearly becomes compromised with aging, and the altered proteostasis has been linked to the gradual deterioration of synaptic connections important for cognition. Poor nutrition is known to impact cognition and many studies suggest natural products promote cognitive health. Here, a dozen natural products were tested for their ability to amplify cathepsin B (CatB), a lysosomal enzyme that has been found to degrade pathogenic proteins and to be synaptoprotective in models of aging-related neurodegenerative disorders. After three daily infusions into hippocampal explants, extracts of bacopa (<i>Bacopa monnieri</i>) and the specific ginseng <i>Panax quinquefolius</i> enhanced the 30-kDa active form of the CatB protease (CatB-30) by over 3-fold, whereas only small increases were produced by another ginseng extract (<i>Panax ginseng</i>) and wild blueberry extract (<i>Vaccinium</i><i>corymbosum</i>). Only <i>P. quinquefolius</i> treatment produced a correlation between enhanced CatB-30 levels and levels of the synaptic proteins GluA1 and synaptophysin. This ginseng extract was also the most effective natural product tested for increasing the autophagy marker LC3-II. To further address the hypothesis that dietary agents activate the CatB autophagy-lysosomal component and enhance synaptic resilience, we tested plant extracts and the exercise mimetic β-GPA in long-term hippocampal slice cultures subjected to a week of proteostatic stress induced by the lysosomotropic compound chloroquine. Note that, similar to the benefits of a healthy diet, exercise is well-known for reducing dementia risk, and the exercise mimetic β-GPA was previously shown in our lab to positively modulate the CatB protease. In the chloroquine-insulted tissue, both <i>P.quinquefolius</i> and β-GPA treatments resulted in significant protection of hippocampal synapses, and <i>V.</i><i>corymbosum</i> extract protected marginally. These results indicate synaptic resilience as being a key factor for brain health through diet and exercise. In recent <i>in&nbsp;vivo</i> studies, our translational research identified selective cognitive defects in middle-aged rodents as compared to respective young groups, and the aging-induced cognitive decline was offset by two tested treatments. The same ginseng extract found to be an effective CatB positive modulator improved behavioral performance in middle-aged Fisher rats (12 months) when supplemented into supplied food pellets for 6 weeks. In a separate study, β-GPA was found to enhanced memory in 10-month-old mice when supplemented into a 6-week feeding schedule. Interestingly, the commonality the two agents have for reducing the aging-related cognitive deficits is similar to the common modulation the agents elicit towards key elements of the autophagy-lysosomal system.