Abstract
Endoplasmic reticulum (ER) stress is involved in various neurodegenerative disorders. We previously found that Capsosiphon fulvescens (C. fulvescens) crude proteins enhance spatial memory by increasing the expression of brain-derived neurotrophic factor (BDNF) in rat dorsal hippocampus. The present study investigated whether the chronic oral administration of hydrophilic C. fulvescens glycoproteins (Cf-hGP) reduces aging-induced cognitive dysfunction by regulating ER stress in the dorsal hippocampus. The oral administration of Cf-hGP (15 mg/kg/day) for four weeks attenuated the aging-induced increase in ER stress response protein glucose-regulated protein 78 (GRP78) in the synaptosome of the dorsal hippocampus; this was attenuated by the function-blocking anti-BDNF antibody (1 μg/μL) and a matrix metallopeptidase 9 inhibitor 1 (5 μM). Aging-induced GRP78 expression was associated with glycogen synthase kinase-3 beta (GSK-3β) (Tyr216)-mediated c-Jun N-terminal kinase phosphorylation, which was downregulated upon Cf-hGP administration. The Cf-hGP-induced increase in GSK-3β (Ser9) phosphorylation was downregulated by inhibiting tyrosine receptor kinase B and extracellular signal-regulated kinase (ERK)1/2 with cyclotraxin-B (200 nM) and SL327 (10 μM), respectively. Cf-hGP administration or the inhibition of ER stress with salubrinal (1 mg/kg, i.p.) significantly decreased aging-induced spatial memory impairment. These findings suggest that the activation of the synaptosomal BDNF-ERK1/2 signaling in the dorsal hippocampus by Cf-hGP attenuates age-dependent ER stress-induced cognitive dysfunction.
Highlights
Aging is a natural process associated with functional and cognitive decline that is closely associated with neurobiological changes in the hippocampus
Cf-hGP administration or the inhibition of endoplasmic reticulum (ER) stress with salubrinal (1 mg/kg, i.p.) significantly decreased aging-induced spatial memory impairment. These findings suggest that the activation of the synaptosomal brain-derived neurotrophic factor (BDNF)-ERK1/2 signaling in the dorsal hippocampus by Cf-hGP attenuates age-dependent ER stress-induced cognitive dysfunction
The Aging-Induced Increase in Glucose-regulated protein 78 (GRP78) Expression in the Dorsal Hippocampus Was Downregulated by Chronic Cf-hGP Administration
Summary
Aging is a natural process associated with functional and cognitive decline that is closely associated with neurobiological changes in the hippocampus. Reduction in volume and vessel degeneration in the hippocampus may contribute to reduced neurogenesis, resulting in cognitive dysfunction [4,5]. These age-associated changes are closely linked to the proteostasis network. Aging-induced protein damage and alterations in the redox status can decrease protein folding capacity, which causes the accumulation of misfolded proteins in the ER lumen and the activation of several signaling pathways, which is known as the ER stress response [6,8,9,10].
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