Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that has been reported as a potential marker for pre-dementia stages of Alzheimer's disease (AD). Longitudinal studies for ...its association with the conversion of mild cognitive impairment to AD is still lacking. This study included n = 268 study participants with subjective cognitive decline (SCD) (n=82), mild cognitive impairment (MCI) (n=98) and AD dementia (n=88) at baseline and two-year follow-up clinical assessments. Serum and cerebrospinal fluid (CSF)NGAL, CSF amyloid beta1-42, total-Tau, and phospho-Tau levels were measured with ELISA analysis. CSF NGAL levels were significantly lower in MCI participants compared to people with SCD at baseline. Lower baseline CSF NGAL levels predicted MCI converters to AD dementia vs. non-converters after 2-years follow-up. A positive correlation between CSF NGAL and amyloid beta1-42 was found particularly in MCI participants at baseline. NGAL in CSF holds potential to be used as a predictive marker for the conversion of MCI to AD dementia and may reflect pathophysiological processes of prodromal AD neuropathology.
Proinflammatory state of the brain increases the risk for seizure development. Neonatal Borna disease virus (BDV)-infection of mice with neuronal overexpression of tumor necrosis factor-α (TNF) was ...used to investigate the complex relationship between enhanced cytokine levels, neurotropic virus infection and reaction pattern of brain cells focusing on its role for seizure induction. Viral antigen and glial markers were visualized by immunohistochemistry. Different levels of TNF in the CNS were provided by the use of heterozygous and homozygous TNF overexpressing mice. Transgenic TNF, total TNF (native and transgenic), TNF-receptor (TNFR1, TNFR2), IL-1 and N-methyl-D-aspartate (NMDA)-receptor subunit 2B (NR2B) mRNA values were measured by real time RT-PCR. BDV-infection of TNF-transgenic mice resulted in non-purulent meningoencephalitis accompanied by epileptic seizures with a higher frequency in homozygous animals. This correlated with lower weight gain, stronger degree and progression of encephalitis and early, strong microglia activation in the TNF-transgenic mice, most obviously in homozygous animals. Activation of astroglia could be more intense and associated with an unusual hypertrophy in the transgenic mice. BDV-antigen distribution and infectivity in the CNS was comparable in TNF-transgenic and wild-type animals. Transgenic TNF mRNA-expression was restricted to forebrain regions as the transgene construct comprised the promoter of NMDA-receptor subunit2B and induced up-regulation of native TNF mRNA. Total TNF mRNA levels did not increase significantly after BDV-infection in the brain of transgenic mice but TNFR1, TNFR2 and IL-1 mRNA values, mainly in the TNF overexpressing brain areas. NR2B mRNA levels were not influenced by transgene expression or BDV-infection. Neuronal TNF-overexpression combined with BDV-infection leads to cytokine up-regulation, CNS inflammation and glial cell activation and confirmed the presensitizing effect of elevated cytokine levels for the development of spontaneous epileptic seizures when exposed to additional infectious noxi.
•TNFR2 plays an important role in memory formation and motor function in young mice.•Aging has differential effects in TNFR2 mediated functions of anxiety-like behavior.•Aging caused memory ...impairment in spatial memory recognition independent of genotype.
TNF-α plays important functional roles in the central nervous system during normal physiological circumstances via intricate signaling mechanisms between its receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Although the roles of TNFR1 and TNFR2 in the diseased brain have received considerable attention, their functions on behavior and cognition in a non-inflammatory physiological aged environment are still unknown. In the present study we investigated the functional roles of TNFR1 and TNFR2 in learning and memory, motor performance and anxiety-like behavior via several behavioral and cognitive assessments in young and aged mice, deficient of either TNFR1 or TNFR2. Results from this study show that deletion of TNFR2 impairs novel object recognition, spatial memory recognition, contextual fear conditioning, motor performance and can increase anxiety-like behavior in young adult mice. Concerning the functions of TNFR1 and TNFR2 functioning in an aged environment, age caused memory impairment in spatial memory recognition independent of genotype. However, both young and aged mice deficient of TNFR2 performed poorly in the contextual fear conditioning test. These mice displayed decreased anxiety-like behavior, whereas mice deficient of TNFR1 were insusceptible to the effect of aging on anxiety-like behavior. This study provides novel knowledge on TNFR1 and TNFR2 functioning in behavior and cognition in young and aged mice in a non-inflammatory physiological environment.
Amyloid oligomers are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases including Alzheimer’s disease. Using MD simulation techniques, we explored the ...contributions of the different structural elements of trimeric and pentameric full-length Aβ1−42 aggregates in solution to their stability and conformational dynamics. We found that our models are stable at a temperature of 310 K, and converge toward an interdigitated side-chain packing for intermolecular contacts within the two β-sheet regions of the aggregates: β1 (residues 18−26) and β2 (residues 31−42). MD simulations reveal that the β-strand twist is a characteristic element of Aβ-aggregates, permitting a compact, interdigitated packing of side chains from neighboring β-sheets. The β2 portion formed a tightly organized β-helix, whereas the β1 portion did not show such a firm structural organization, although it maintained its β-sheet conformation. Our simulations indicate that the hydrophobic core comprising the β2 portion of the aggregate is a crucial stabilizing element in the Aβ aggregation process. On the basis of these structure−stability findings, the β2 portion emerges as an optimal target for further antiamyloid drug design.
Major Depressive Disorder (MDD) is a heterogeneous disorder with a considerable symptomatic overlap with other psychiatric and somatic disorders. This study aims at providing evidence for association ...of a set of serum and urine biomarkers with MDD. We analyzed urine and serum samples of 40 MDD patients and 47 age- and sex-matched controls using 40 potential MDD biomarkers (21 serum biomarkers and 19 urine biomarkers). All participants were of Caucasian origin. We developed an algorithm to combine the heterogeneity at biomarker level. This method enabled the identification of correlating biomarkers based on differences in variation and distribution between groups, combined the outcome of the selected biomarkers, and calculated depression probability scores (the “bio depression score”). Phenotype permutation analysis showed a significant discrimination between MDD and euthymic (control) subjects for biomarkers in urine (P < .001), in serum (P = .02) and in the combined serum plus urine result (P < .001). Based on this algorithm, a combination of 8 urine biomarkers and 9 serum biomarkers were identified to correlate with MDD, enabling an area under the curve (AUC) of 0.955 in a Receiver Operating Characteristic (ROC) analysis. Selection of either urine biomarkers or serum biomarkers resulted in AUC values of 0.907 and 0.853, respectively. Internal cross-validation (5-fold) confirmed the association of this set of biomarkers with MDD.
•This study investigates biomarker panels for Major Depressive Disorder (MDD).•The biomarker panels were assessed in serum as well as in urine.•A new method was used to combine results of multiple biomarkers into a single score.•This scoring method is based on differences in variation and distribution.•A panel of 9 serum and 8 urine biomarkers was identified to correlate with MDD.
Neuroinflammation has been implicated in the pathology of various psychiatric and neurodegenerative disorders. Accumulating evidence suggests that food components can modulate inflammatory processes, ...and therefore it could be hypothesized that such nutrients might exhibit therapeutic efficacy against these brain diseases. Rice bran is often discarded as a waste product, although it contains a wide range of potentially useful substances. Several rice fiber components from rice bran have been described as having antiinflammatory properties. This review summarizes the evidence supporting a modulatory effect of rice fiber components on symptoms in several animal models for neuroinflammation. In vitro studies on immune cells and in vivo studies on nutritional intervention in animal models of central and peripheral inflammation are discussed in the context of the potential use of rice fiber components for prevention and treatment of brain diseases in which neuroinflammation is involved.
Highlight • Depression in patients with chronic heart failure is associated with elevated serum NGAL levels, independent of clinical severity of the underlying disease.
Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases ...(like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker (11)C-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior.
Nitric oxide (NO) regulation plays a critical role in cardiovascular diseases including heart failure (HF). Markers of NO dysregulation have been found in individuals with depression without ...cardiovascular disease. Because depression is associated with poor HF outcomes, the present study tested the hypothesis that depression is associated with a dysregulated NO pathway in patients with HF.
Serum levels of NO regulation (L-arginine, asymmetric dimethylarginine ADMA, and symmetric dimethylarginine SDMA) and oxidative stress (isoprostane 8-epi prostaglandin F2α) were measured in 104 patients with HF (mean standard deviation age = 65.7 8.4 years, 28% women) at baseline and 12 months. Depressive symptoms were measured using the Beck Depression Inventory. The associations between depressive symptoms with markers of NO regulation were examined with mixed-model analysis, adjusted for age, sex, time of assessment, left ventricular ejection fraction, creatinine, and hypertension.
Depressive symptoms were correlated with a lower L-arginine/ADMA ratio (r = -0.22, p = .003) and higher SDMA levels (r = 0.28, p < .001). Associations were similar for somatic depressive symptoms and cognitive-affective symptoms (L-arginine/ADMA ratio: r = -0.20 p = .009 versus r = -0.19 p = .013; ADMA: r = 0.16 p = .043 versus r = 0.10 p = .20; SDMA: r = 0.27 p < .001 versus r = 0.22 p = .005, respectively). No associations were found between depressive symptoms and isoprostane. The association between depression and the L-arginine/ADMA ratio remained significant in multivariate adjusted models.
Depressive symptoms were associated with markers of NO dysregulation, particularly the L-arginine/ADMA ratio and SDMA, in patients with HF. The lower L-arginine/ADMA ratio indicates less available NO, suggesting that NO-related endothelial dysfunction may play a role in the adverse risk of HF progression associated with depression.
PDF
