Prions have been extensively studied since they represented a new class of infectious agents, the pathogenic prion protein (PrPSc). However, a question on the physiological function of the normal prion protein (PrPC) remains unresolved. Previously, we established new PrP–deficient cell lines from Zürich I mice (Zür I PrP–/–) to settle the problem of Rikn PrP–/– cell model which expresses the doppel (Dpl). We used the new cell lines, Zpl 2–1, 2–4, 3–4 (Zür I, PrP–/–) and ZW 13–1, 13–2, 13–3 (ICR, PrP+/+) to investigate cDNA gene expression profiles. Also Hpl 3–4 (Rikn, PrP–/–) and HW 8–2 (C57BL6J, PrP+/+) were used to compare gene expression pattern with Zpl and ZW cell lines. Twelve–month–old brains of Zür I, ICR, Rikn, and C57BL6J were used for in vivo experiments. cDNA gene microarray was used to investigate and compare gene expression profiles of PrP–/– and PrP+/+ cell lines of mice. Reverse transcriptase polychain reaction (RT–PCR) was performed to confirm the results of gene microarray data. Sequentially, DNA sequencing was followed to confirm the RT–PCR results. In this study, we performed gene microarray using newly established PrP–/– cell lines, brains of PrP–/– mice, and their wild types to study functional loss of PrPC. Using a large–scale gene array–based approach, which covers 40,000 characterized genes, we identified 39 genes in PrP–/– cell lines and 52 genes in PrP–/– mice which showed different expression levels compared to controls at least 8–fold and 2–fold, respectively. In addition, 12 genes were identified to have similar expression patterns in both PrP–/– cell lines of mice. Most of the genes that showed different expression were associated with signal transduction, the immune response, mitochondrial function, and transcription. This study suggests that PrPC is related to protecting function against damages and provides the diagram of the physiological pathway of PrPC. This work was supported by the International Research Internship Program of the Korea Science and Engineering Foundation (KOSEF).
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by memory impairment that significantly interferes with daily life. Therapeutic options for AD that substantively modify disease progression remain a critical unmet need. In this regard, the gut microbiota is crucial in maintaining human health by regulating metabolism and immune responses, and increasing evidence suggests that probiotics, particularly beneficial bacteria, can enhance memory and cognitive functions. Recent studies have highlighted the positive effects of Bifidobacterium breve MCC1274 (B. breve MCC1274) on individuals with mild cognitive impairment (MCI) and schizophrenia. Additionally, oral supplementation with B. breve MCC1274 has been shown to effectively prevent memory decline in AppNL-G-F mice. In relation to Alzheimer’s pathology, oral supplementation with B. breve MCC1274 has been found to reduce amyloid-β (Aβ) accumulation and tau phosphorylation in both AppNL-G-F and wild-type (WT) mice. It also decreases microglial activation and increases levels of synaptic proteins. In this review, we examine the beneficial effects of B. breve MCC1274 on AD, exploring potential mechanisms of action and how this probiotic strain may aid in preventing or treating the disease. Furthermore, we discuss the broader implications of B. breve MCC1274 for improving overall host health and provide insights into future research directions for this promising probiotic therapy.
The PMCA (protein misfolding cyclic amplification) technique has been shown to drive the amplification of misfolded prion protein by PrP(Sc) seeds during several cycles of incubation-sonication. Here, we report that cyclic amplification of normal hamster brain homogenates treated with a number of transition metals (manganese [Mn], copper [Cu], and iron [Fe]) leads to conversion of PrP(C) into protease-resistant PrP(res). The efficiency of PrP(res) formation and the glycoforms induced by Mn were different from those obtained by Cu and Fe. Previous results have shown higher Mn and lower Cu levels in the affinity-purified PrP(Sc) from the brain of prion diseases compared with normal hamster brain homogenates. We focused on Mn because we observed higher levels of Mn in whole brain, mitochondria, and scrapie-associated fibril-enriched fractions from the brains of animals with prion disease. In the presence of minute quantities of Mn-induced PrP(res) template with a large amount of PrP(C), PrP(res) amplification is observed. A metal chelater, EDTA reverses the effect of Mn on PrP(res) amplification, suggesting that Mn may play a role in the formation of PrP(res). It has been proposed that metal-catalyzed oxidation of PrP leads to the oxidation of amino acids and extensive aggregation of oxidized PrP. Carboxyl acids such as deoxycholic acid (DA) are oxidized molecules produced by 3' oxidation pathway. In in vitro studies, the potent effect of Mn on PrP(res) amplification is augmented by DA in a dose-dependent manner. On the basis of the evidence of the elevated Mn levels in scrapie-associated fibril (SAF)-enriched preparations from the brains of animals with prion disease, Mn-loaded PrP and oxidized molecules such as carboxyl acids may contribute to the formation of the scrapie isoform of PrP in prion diseases.
Ecklonia stolonifera is a brown alga that was shown to have antioxidant, anti-inflammatory, tyrosinase inhibitory, and chemopreventive activities. However, the molecular mechanisms underlying its anti-inflammatory activity remain unclear. In this study, we investigated the molecular mechanism of the anti-inflammatory action of E. stolonifera ethanolic extracts (ESE) using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. ESE inhibited LPS-induced nitric oxide (IC50 = 72 ± 1.9 μg/mL) and prostaglandin E2 (IC50 = 98 ± 5.3 μg/mL) production in a dose-dependent manner and suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 cells. ESE also reduced the production of pro-inflammatory cytokines in LPS-stimulated RAW 264.7 cells. LPS-induced nuclear factor-κB (NF-κB) transcriptional activity and NF-κB translocation into the nucleus were significantly inhibited by ESE treatment through the prevention of the degradation of inhibitor κB-α. Moreover, ESE inhibited the activation of Akt, ERK, JNK1/2, and p38 MAPK in LPS-stimulated RAW 264.7 cells. The main components with anti-inflammatory activity in ESE were identified as phlorofucofuroeckol A and B based on the inhibition of NO production. Our results indicate that ESE can be considered as a potential source of therapeutic agents for inflammatory diseases.
Previous studies have reported that inbred SAM mouse strains have remarkedly different characteristics in a variety of parameters: especially in concentration of infectious murine leukemia viruses (MuLV). To elucidate the effect of higher titer of MuLV in brains of SAMP8 has on the clinical changes seen in this strain, we established astrocyte cell lines from SAMR1 and SAMP8 mice. MuLV-negative astrocyte cell lines established from ICR mice served as controls. Comparison of these cell lines showed differences in: 1) morphology, 2) replication rates of cells and final cell concentrations, 3) levels of the capsid antigen CAgag in both cell lysates and in culture media, 4) expression of genomic retroelements, 5) the number of virus particles, 6) titer of infectious virus. The results indicate that there are profound differences in the MuLV expression in SAMR1 and SAMP8 astrocytes; the cell lines we established in this study may provide a useful model to explore the functions and effects of murine endogenous retrovirus.
Background and purpose The loss of retinal ganglion cells observed in Alzheimer's disease (AD) may be attributable to a neurodegeneration of the neuro-retinal structure. Amnestic mild cognitive impairment (aMCI) has been considered a prodromal stage of AD. We evaluated retinal thicknesses in patients with aMCI and AD compared to healthy controls using spectral-domain optical coherence tomography (OCT) to investigate whether changes in retinal thickness are correlated with the clinical severity of dementia. Methods Patients with aMCI (n = 14), mild to moderate AD (n = 7), severe AD (n = 9), and age-matched controls (n = 17) underwent neuro-ophthalmologic examinations. Global deterioration scale (GDS), clinical dementia rating (CDR), and mini-mental status examination (MMSE) were used to evaluate the clinical overall severity of dementia. The thicknesses of the peripapillary retinal nerve fiber layer (RNFL), total macula, and macular ganglion cell-inner plexiform layer (GC-IPL) were measured using Cirrus HD-OCT. Results The severe AD group had overall significantly thinner GC-IPL, total macula, and peripapillary RNFL compared to the controls (p<0.05). In the mild to moderate AD group, the total macula, average RNFL, and superior RNFL thickness were each significantly reduced compared to controls (p<0.05). The aMCI group had reduced total macula, average RNFL, and inferior RNFL thickness, but there were no significant differences compared to the controls. The GDS and CDR scores had a negative correlation with the thickness of the GC-IPL and the total macula. The MMSE scores had a positive correlation with both the total macular and average RNFL thickness, when adjusted for age (p<0.05). Conclusions This study confirmed that retinal thickness is decreased in AD patients. There is a correlation between reduced retinal thickness and the clinical severity of dementia.
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