Home » SLAM-DUNC Abstracts 2022 » Non-pharmacologic avenue targets the autophagy-lysosomal pathway to offset the synaptic decline in a brain explant model of age-related proteostatic stress

Non-pharmacologic avenue targets the autophagy-lysosomal pathway to offset the synaptic decline in a brain explant model of age-related proteostatic stress

Almeida MF, Rentschler KM, Farizatto KLG, Pait MC, and Bahr BA.

Biotechnology Research and Training Center – University of North Carolina – Pembroke

Diet and aging influence cognition and the autophagy-lysosomal protein clearance pathway, a pathway manipulated by synaptic activity and important for memory (Kulkarni et al. 2021-J Cell Biol 220:e202002084). Understanding protein clearance systems and their crosstalk are important to identify therapeutic avenues for Alzheimer’s disease (AD) and other proteinopathies (Farizatto et al. 2017-PLoS ONE 12:e0182895; Boland et al. 2018-Nat Rev Drug Discov 17:660). Enhancing the lysosomal protease cathepsin B (CatB) improves protein clearance and cognitive function in models of AD, α-synucleinopathy, and mild cognitive impairment (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).

Here, we tested whether the synapto-protective CatB effects elicited by pharmacological modulators also occurs with plant extracts. American ginseng and bacopa enhanced the 30-kDa active form of CatB over 3-fold in hippocampal explants, whereas only small increases were produced by Asian ginseng and blueberry extracts. Both pharmacological and non-pharmacological agents induced associations between CatB substrate degradation, synaptic resilience indicators, and enhanced conversion of LC3I to LC3II. American ginseng was the only extract with correlating effects on CatB and synaptic protein levels. Extended infusion with American ginseng also protected against the synaptic decline found in hippocampal slices subjected to proteostatic stress by the lysosomal inhibitor chloroquine. In this model, pre- and postsynaptic staining in dendritic fields was preserved by American ginseng. These results indicate that the specific American ginseng extract influences proteostasis, and suggests that synaptic resilience is a key factor by which certain diets favor cognitive maintenance.