The aim of this study was to perform a genome-wide expression analysis of whole-blood samples from people with optic neuritis (ON) and to determine differentially expressed mRNAs compared to healthy control subjects. The study included eight people with acute ON and six healthy control subjects. Gene expression was analyzed using DNA microarrays for whole-human-genome analysis, which contain 54,675 25-base pairs. The additional biostatistical analysis included gene ontology analysis and gene set enrichment analysis (GSEA). Quantitative RT-PCR (qPCR) was used to confirm selected differentially expressed genes. In total, 722 differently expressed genes were identified, with 377 exhibiting increased, and 345 decreased, expression. Gene ontology analysis and GSEA revealed that protein phosphorylation and intracellular compartment, apoptosis inhibition, pathways involved in cell cycles, T and B cell functions, and anti-inflammatory central nervous system (CNS) pathways are implicated in ON pathology. qPCR confirmed the differential expression of eight selected genes, with SLPI, CR3, and ITGA4 exhibiting statistically significant results. In conclusion, whole-blood gene expression analysis showed significant differences in the expression profiles of people with ON compared to healthy control subjects. Additionally, pathways involved in T cell regulation and anti-inflammatory pathways within CNS were identified as important in the early phases of MS. Full article

Type 2 diabetes mellitus increases the risk of sporadic Alzheimer’s disease (sAD), and antidiabetic drugs, including the sodium–glucose cotransporter inhibitors (SGLTI), are being studied as possible sAD therapy. We have explored whether the SGLTI phloridzin may influence metabolic and cognitive parameters in a rat model of sAD. Adult male Wistar rats were randomized to a control (CTR), an sAD-model group induced by intracerebroventricular streptozotocin (STZ-icv; 3 mg/kg), a CTR+SGLTI, or an STZ-icv+SGLTI group. Two-month-long oral (gavage) SGLTI treatment (10 mg/kg) was initiated 1 month after STZ-icv and cognitive performance tested prior to sacrifice. SGLTI treatment significantly decreased plasma glucose levels only in the CTR group and failed to correct STZ-icv-induced cognitive deficit. In both the CTR and STZ-icv groups, SGLTI treatment diminished weight gain, decreased amyloid beta (Aβ) 1-42 in duodenum, and decreased the plasma levels of total glucagon-like peptide 1 (GLP-1), while the levels of active GLP-1, as well as both total and active glucose-dependent insulinotropic polypeptide, remained unchanged, compared to their respective controls. The increment in GLP-1 levels in the cerebrospinal fluid and its effect on Aβ 1-42 in duodenum could be one of the molecular mechanisms by which SGLTIs indirectly induce pleiotropic beneficial effects. Full article

The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some aspects of in vivo tau spreading have been replicated in transgenic mice models expressing a mutated human MAPT (tau) gene and in wild-type mice. In this study, we aimed to characterize the propagation of different forms of tau species in non-transgenic 3–4 months old wild-type rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether different variants of the inoculated human tau protein, tau fibrils, and tau oligomers, would induce similar neurofibrillary changes and propagate in an AD-related pattern, and how tau-related pathological changes would correlate with presumed cognitive impairment. We injected human tau fibrils and tau oligomers stereotaxically into the mEC and examined the distribution of tau-related changes at 3 days and 4, 8, and 11 months post-injection using antibodies AT8 and MC1, which reveal early phosphorylation and aberrant conformation of tau, respectively, HT7, anti-synaptophysin, and the Gallyas silver staining method. Human tau oligomers and tau fibrils exhibited some similarities and some differences in their ability to seed and propagate tau-related changes. Both human tau fibrils and tau oligomers rapidly propagated from the mEC anterogradely into the hippocampus and various parts of the neocortex. However, using a human tau-specific HT7 antibody, 3 days post-injection we found inoculated human tau oligomers in the red nucleus, primary motor, and primary somatosensory cortex, a finding not seen in animals inoculated with human tau fibrils. In animals inoculated with human tau fibrils, 3 days post-injection the HT7 antibody showed fibrils in the pontine reticular nucleus, a finding explained only by uptake of human tau fibrils by incoming presynaptic fibers to the mEC and retrograde transport of inoculated human tau fibrils to the brainstem. Rats inoculated with human tau fibrils showed as early as 4 months after inoculation a spread of phosphorylated tau protein at the AT8 epitopes throughout the brain, dramatically faster propagation of neurofibrillary changes than with human tau oligomers. The overall severity of tau protein changes 4, 8, and 11 months after inoculation of human tau oligomers and tau fibrils correlated well with spatial working memory and cognition impairments, as measured by the T-maze spontaneous alternation, novel object recognition, and object location tests. We concluded that this non-trangenic rat model of tauopathy, especially when using human tau fibrils, demonstrates rapidly developing pathologic alterations in neurons, synapses, and identifiable pathways together with cognitive and behavioral changes, through the anterograde and retrograde spreading of neurofibrillary degeneration. Therefore, it represents a promising model for future experimental studies of primary and secondary tauopathies, especially AD. Full article

Cognitive deficit is a frequent non-motor symptom in Parkinson’s disease (PD) with an unclear pathogenesis. Recent research indicates possible involvement of insulin resistance and glutamate excitotoxicity in PD development. We investigated cognitive performance and the brain glutamate and insulin signaling in a rat model of PD induced by bilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA). Cognitive functions were assessed with Passive Avoidance (PA) and Morris Water Maze (MWM) tests. The expression of tyrosine hydroxylase (TH) and proteins involved in insulin (insulin receptor - IR, phosphoinositide 3 kinase - pI3K, extracellular signal-regulated kinases-ERK) and glutamate receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptos-AMPAR, N-methyl-D-aspartate receptor - NMDAR) signaling was assessed in the hippocampus (HPC), hypothalamus (HPT) and striatum (S) by immunofluorescence, Western blot and enzyme-linked immunosorbent assay (ELISA). Three months after 6-OHDA treatment, cognitive deficit was accompanied by decreased AMPAR activity and TH levels (HPC, S), while levels of the proteins involved in insulin signaling remained largely unchanged. Spearman’s rank correlation revealed a strong positive correlation for pAMPAR-PA (S), pNMDAR-pI3K (HPC) and pNMDAR-IR (all regions). Additionally, a positive correlation was found for TH-ERK and TH-pI3K, and a negative one for TH-MWM/errors and pI3K-MWM/time (S). These results suggest a possible association between brain glutamate (but not insulin) signaling dysfunction and cognitive deficit in a rat PD model, detected three months after 6-OHDA treatment. Full article

The prevalence of Alzheimer’s disorder (AD) is increasing worldwide, and the co-morbid anxiety is an important, albeit often neglected problem, which might appear early during disease development. Animal models can be used to study this question. Mice, as prey animals, show an innate defensive response against a predator odor, providing a valuable tool for anxiety research. Our aim was to test whether the triple-transgenic mice model of AD shows signs of innate anxiety, with specific focus on the temporal appearance of the symptoms. We compared 3xTg-AD mice bearing human mutations of amyloid precursor protein, presenilin 1, and tau with age-matched controls. First, separate age-groups (between 2 and 18 months) were tested for the avoidance of 2-methyl-2-thiazoline, a fox odor component. To test whether hypolocomotion is a general sign of innate anxiety, open-field behavior was subsequently followed monthly in both sexes. The 3xTg-AD mice showed more immobility, approached the fox odor container less often, and spent more time in the avoidance zone. This effect was detectable already in two-month-old animals irrespective of sex, not visible around six months of age, and was more pronounced in aged females than males. The 3xTg-AD animals moved generally less. They also spent less time in the center of the open-field, which was detectable mainly in females older than five months. In contrast to controls, the aged 3xTg-AD was not able to habituate to the arena during a 30-min observation period irrespective of their sex. Amyloid beta and phospho-Tau accumulated gradually in the hippocampus, amygdala, olfactory bulb, and piriform cortex. In conclusion, the early appearance of predator odor- and open space-induced innate anxiety detected already in two-month-old 3xTg-AD mice make this genetically predisposed strain a good model for testing anxiety both before the onset of AD-related symptoms as well as during the later phase. Synaptic dysfunction by protein deposits might contribute to these disturbances. Full article

Due to the increasing number of progressive dementias in the population, numerous studies are being conducted that seek to determine risk factors, biomarkers and pathological mechanisms that could help to differentiate between normal symptoms of aging, mild cognitive impairment (MCI) and dementia. The aim of this study was to investigate the possible association of levels of BDNF and COMT gene expression and methylation in peripheral blood cells with the development of Alzheimer’s disease (AD). Our results revealed higher expression levels of BDNF (p < 0.001) in MCI subjects compared to individuals diagnosed with AD. However, no difference in COMT gene expression (p = 0.366) was detected. DNA methylation of the CpG islands and other sequences with potential effects on gene expression regulation revealed just one region (BDNF_9) in the BDNF gene (p = 0.078) with marginally lower levels of methylation in the AD compared to MCI subjects. Here, we show that the level of BDNF expression in the periphery is decreased in subjects with AD compared to individuals with MCI. The combined results from the gene expression analysis and DNA methylation analysis point to the potential of BDNF as a marker that could help distinguish between MCI and AD patients. Full article

Traumatic brain injuries (TBI) and posttraumatic stress disorder (PTSD) are commonly observed comorbid occurrences among military service members and veterans (SMVs). In this cross-sectional study, SMVs with a history of TBI were stratified into symptomatic and asymptomatic PTSD groups based on posttraumatic stress checklist-civilian (PCL-C) total scores. Blood-based biomarkers were assessed, and significant differential markers were associated with scores from multiple neurobehavioral self-report assessments. PCL-C cutoffs were total scores >50 (PTSD symptomatic) and <25 (asymptomatic). Cytokines IL6, IL8, TNFα, and IL10 were significantly elevated (p < 0.05–0.001) in the TBI+/PTSD symptomatic group compared to the TBI+/asymptomatic group. Cytokine levels of IL8, TNFα, and IL10 were strongly associated with PCL-C scores (0.356 < r > 0.624 for all, p < 0.01 for all), while TNFα and IL10 were additionally associated with NSI totals (r = 0.285 and r = 0.270, p < 0.05, respectively). This is the first study focused on PTSD symptom severity to report levels of circulating pro-inflammatory IL8, specifically in SMVs with TBI. These data suggest that within the military TBI population, there are unique cytokine profiles that relate to neurobehavioral outcomes associated with TBI and PTSD. Full article

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), which leads to disturbances in the conduction of nerve impulses, cognitive impairment, sensory and motor disturbances, as well as depressive symptoms. MS remains an incurable disease with a difficult diagnosis and unclear etiology. The aim of the analysis was to identify SNPs that may potentially be associated with an increased risk of developing MS. Blood samples were obtained from patients with MS (194 subjects) and age-matched healthy controls (188 subjects). The polymorphic variant frequencies of rs197412 T>C in GEMIN3, rs7813 G>A in GEMIN4, rs1106042 G>A in HIWI, rs10719 A>C in DROSHA, rs3742330 A>G in DICER1, rs11077 T>G in XPO5, rs14035 C>T in RAN, rs636832 G>A in AGO1 were determined in DNA using real-time PCR TaqMan^® SNP Genotyping Assay. Our findings indicate that the GG AGO1 rs636832 and AA GEMIN4 rs7813 genotypes were associated with an increased risk of MS. Although our findings provide a clearer understanding of the pathogenesis of MS, further investigations are needed to better understand their potential for the evaluation of other miRNA processing genes believed to be associated with MS etiology. Full article

Earlier we showed that derivatives of hydroxycinnamic acids prevent amyloid transformation of alpha-synuclein and prion protein. The aim of this work was to determine the content of 3-hydroxycinnamic acid derivatives in coffee extracts and to evaluate their activity in relation to alpha-synuclein amyloid aggregation. Hydroxycinnamic acid derivatives were identified in aqueous and ethanol extracts of coffee beans by quantitative mass spectrometric analysis. Only 3,4-dimethoxycinnamic acid (13–53 μg/mL) was detected in significant amounts in the coffee extracts, while ferulic acid was present in trace amounts. In addition, 3-methoxy-4-acetamidoxycinnamic acid (0.4–0.8 μg/mL) was detected in the roasted coffee extracts. The half-maximum inhibitory concentrations of alpha-synuclein fibrillization reaction in the presence of coffee extracts, as well as inhibitory constants, were determined using thioflavin T assay. The inhibitory effect of black and green coffee extracts on alpha-synuclein fibrillization is dose-dependent, and in a pairwise comparison, the constants of half-maximal inhibition of fibrillization for green coffee extracts are comparable to or greater than those for black coffee. Thus, coffee extracts prevent pathological transformation of alpha-synuclein in vitro, probably due to the presence of 3,4-dimethoxycinnamic acid in them. Consequently, coffee drinks and coffee extracts can be used for the prevention of synucleinopathies including Parkinson’s disease. Full article

The role of metals in the pathogenesis of Alzheimer’s disease (AD) is still debated. Although previous research has linked changes in essential metal homeostasis and exposure to environmental heavy metals to the pathogenesis of AD, more research is needed to determine the relationship between metals and AD. In this review, we included human studies that (1) compared the metal concentrations between AD patients and healthy controls, (2) correlated concentrations of AD cerebrospinal fluid (CSF) biomarkers with metal concentrations, and (3) used Mendelian randomization (MR) to assess the potential metal contributions to AD risk. Although many studies have examined various metals in dementia patients, understanding the dynamics of metals in these patients remains difficult due to considerable inconsistencies among the results of individual studies. The most consistent findings were for Zn and Cu, with most studies observing a decrease in Zn levels and an increase in Cu levels in AD patients. However, several studies found no such relation. Because few studies have compared metal levels with biomarker levels in the CSF of AD patients, more research of this type is required. Given that MR is revolutionizing epidemiologic research, additional MR studies that include participants from diverse ethnic backgrounds to assess the causal relationship between metals and AD risk are critical. Full article

The central nervous system (CNS) injury, which occurs because of mechanical trauma or ischemia/hypoxia, is one of the main causes of mortality and morbidity in the modern society. Until know, despite the fact that numerous preclinical and clinical studies have been undertaken, no significant neuroprotective strategies have been discovered that could be used in the brain trauma or ischemia treatment. Although there are many potential explanations for the failure of those studies, it is clear that there are questions regarding the use of experimental models, both in vivo and in vitro, when studying CNS injury and searching new therapeutics. Due to some ethical issues with the use of live animals in biomedical research, implementation of experimental strategies that prioritize the use of cells and tissues in the in vitro environment has been encouraged. In this review, we examined some of the most commonly used in vitro models and the most frequently utilized cellular platforms in the research of traumatic brain injury and cerebral ischemia. We also proposed some future strategies that could improve the usefulness of these studies for better bench-to-bedside translational outcomes. Full article