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This study was designed to examine the mechanisms underlying decline of stress resilience in aged rats from the perspective of CP-CSF-hippocampus. Male Wistar rats (7–8 weeks old or 20 months old) were subjected to chronic unpredictable mild stress (CUMS) for 6 weeks. The behavioral tests were conducted to assess anxiety, depression and cognitive function. Hippocampal neurogenesis, apoptosis and synaptic plasticity were detected by western blot (WB) and/or immunofluorescence (IF) assay. Differential expression of growth factors (GFs) and axon guidance proteins (AGPs) in CSF was analyzed using the quantitative proteomics approach. IF and WB were performed to detect expression of occludin-1, Ki-67/Transthyretin, and folate transporters in choroid plexus (CP). Decreased proliferation, impaired structure and transport function of CP were correlated with CSF composition alterations in stressed aging rats, including reduced 5-Methyltetrahydrofolate, growth factors and axon growth factors. Nutritional support of CSF upon hippocampus was attenuated, therefore affecting hippocampal plasticity. It has led to depression-like behaviors and cognitive deficits in stressful aged rats. Keeping normal structure and function of CP-CSF system may be a practical strategy for neuropsychological disorders in the elderly. This work provides evidential basis for CP transplant and CSF replacement therapy in future studies. [ABSTRACT FROM AUTHOR]

Cognitive deficiency is one of the fundamental characteristics of late-onset depression (LOD). Luteolin (LUT) possesses antidepressant, anti-aging, and neuroprotective properties, which can dramatically enhance cognition. The altered composition of cerebrospinal fluid (CSF), which is involved in neuronal plasticity and neurogenesis, directly reflects the physio-pathological status of the central nervous system. It is not well known whether the effect of LUT on LOD is in association with a changed CSF composition. Therefore, this study first established a rat model of LOD and then tested the therapeutic effects of LUT using several behavioral approaches. A gene set enrichment analysis (GSEA) was used to evaluate the CSF proteomics data for KEGG pathway enrichment and Gene Ontology annotation. We combined network pharmacology and differentially expressed proteins to screen for key GSEA–KEGG pathways as well as potential targets for LUT therapy for LOD. Molecular docking was adopted to verify the affinity and binding activity of LUT to these potential targets. The outcomes demonstrated that LUT improved the cognitive and depression-like behaviors in LOD rats. LUT may exert therapeutic effects on LOD through the axon guidance pathway. Five axon guidance molecules—EFNA5, EPHB4, EPHA4, SEMA7A, and NTNG—as well as UNC5B, L1CAM, and DCC, may be candidates for the LUT treatment of LOD. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate potential biomarkers of depression and targets of antidepressants from the perspective of hippocampal endoplasmic reticulum stress (ERS) based on cerebrospinal fluid (CSF) proteomics. Firstly, a six-week depression model was established and treated with fluoxetine (FLX). We found antidepressant-FLX could ameliorate depression-like behaviors and cognition in depressed rats caused by chronic unpredictable mild stress (CUMS). FLX significantly increased neuronal numbers in dentate gyrus (DG) and CA3 regions of hippocampus. CSF proteome data revealed thirty-seven differentially expressed proteins (DEPs) co-regulated by CUMS and FLX, including GRP94 and EIF2α. Results of Gene Oncology (GO) annotation and KEGG pathway enrichment for DEPs mainly included PERK-mediated unfolded protein response, endoplasmic reticulum, and translational initiation. The expression levels of GRP94, p-PERK, p-EIF2α, CHOP and Caspase-12 were increased in hippocampus of CUMS rats, and FLX worked the opposite way. FLX had strong affinity and binding activity with GRP94 protein, and four key proteins on the PERK pathway (PERK, EIF2α, p-EIF2α, CHOP). We proposed that FLX may exert antidepressant effects and neuroprotective action by alleviating excessive activation of the hippocampal PERK pathway and reducing neuronal deficits in depressed rats. PERK, EIF2α, p-EIF2α, and CHOP may be potential targets for antidepressant-FLX. GRP94 in CSF may be a potential biomarker of depression and the therapeutic effects of antidepressants. [Display omitted] • Increased GRP94 and EIF2α in cerebrospinal fluid of CUMS rats. • Excessive endoplasmic reticulum stress in hippocampus of CUMS rats. • Overactivation of the PERK pathway in the hippocampus of CUMS rats. • High correlation between PERK pathway-related proteins and NeuN numbers. • High correlation between PERK pathway-related proteins and behavioral data. [ABSTRACT FROM AUTHOR]