Capsosiphon fulvescens Glycoproteins Enhance Probiotics-Induced Cognitive Improvement in Aged Rats.

Jeong Hwan Oh,Youn Hee Choi,Taek-Jeong Nam

doi:10.3390/nu12030837

Abstract

Aging-induced cognitive dysfunction can be regulated by probiotics through bidirectional communication with the brain. This study aimed to investigate whether Capsosiphon fulvescens glycoproteins (Cf-hGP) enhanced probiotic-induced improvement of memory in aged rats and the underlying mechanism in the dorsal hippocampus. Cf-hGP were isolated using lectin resin. Cf-hGP (15 mg/kg/day) and/or Lactobacillus plantarum (L. plantarum) (109 CFU/rat/day) were orally administered once a day for 4 weeks. Co-treatment with Cf-hGP and L. plantarum synergistically improved spatial memory in aged rats, which was overturned by functional blocks of brain-derived neurotrophic factor (BDNF) signaling. Increases in BDNF expression and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation were accompanied by mono- and/or co-administration in the dorsal hippocampus, while c-Jun N-terminal kinase (JNK) phosphorylation and glucose-regulated protein 78 expression were decreased. These synergistic effects were downregulated by blocks of BDNF/Nrf2-mediated signaling. In particular, co-treatment, not mono-treatment, reduced phosphorylation of eukaryotic elongation factor 2 (eEF2) regulated by eEF2 kinase and protein phosphatase 2A. Additionally, co-treatment downregulated the interaction between eEF2 kinase and JNK. These data demonstrated that cognitive impairment in aged rats was synergistically diminished by co-treatment with Cf-hGP and L. plantarum through BDNF-mediated regulation of Nrf2 and eEF2 signaling pathways in the dorsal hippocampus.

Highlights

Aging is a natural process associated with functional and cognitive decline, which is closely associated with neurobiological changes in the hippocampus, including a decrease in the number of newborn neurons in the subgranular zone of the hippocampus [1,2,3]
Since brain-derived neurotrophic factor (BDNF) induces activation of signaling of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which is a key regulator of antioxidant protein expression against oxidative damage and endoplasmic reticulum (ER) stress [30], we further investigated whether the synergistic enhancement of BDNF signaling regulated Nrf2 and Jun N-terminal kinase (JNK) phosphorylation, and whether activation of BDNF-mediated Nrf2 signaling was associated with the co-treatment-induced decrease in JNK phosphorylation and ER stress response
The co-treatment with Cf-hGP and L. plantarum significantly increased eEF2K phosphorylation and inactivated eEF2K, which reduced its interaction with JNK and JNK phosphorylation in the dorsal hippocampus (Figure 5B,C). These data demonstrated that the activation of hippocampal BDNF signaling by the co-treatment downregulated phosphorylation of eukaryotic elongation factor 2 (eEF2) linked to the eEF2K and phosphatase 2A (PP2A) in the dorsal hippocampus, suggesting that regulation of eEF2 phosphorylation may be a key underlying mechanism of enhancing the synergistic effects of Cf-hGP on the cognitive function in aged rats. These data demonstrate that chronic co-administration of Cf-hGP with L. plantarum could synergistically improve the cognitive function in aged rats compared to any mono-treatment through activation of BDNF-mediated Nrf2 and eEF2 signaling in the dorsal hippocampus (Figure 6)

Summary

Introduction

Aging is a natural process associated with functional and cognitive decline, which is closely associated with neurobiological changes in the hippocampus, including a decrease in the number of newborn neurons in the subgranular zone of the hippocampus [1,2,3]. Age-related neuroplasticity is closely linked to the microbiota-gut-brain axis, as well as to the proteostasis network [6]. Many studies have shown that the gut-brain neural circuits affected by probiotics contribute to cognitive function, emotional disorders, such as anxiety and depression, and neurodegenerative diseases through direct and indirect pathways [8,9,10,11]. These effects of probiotics on the nervous system are associated with neurotrophic factors [12,13]

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