The three isoforms of apolipoprotein (apo) E are strongly associated with different risks for Alzheimer's disease: apoE4>apoE3>apoE2. Here, we show at physiological salt concentrations and pH that native tetramers of apoE form soluble aggregates in vitro that bind the amyloid dyes thioflavin T and Congo red. However, unlike classic amyloid fibrils, the aggregates adopt an irregular protofilament-like morphology and are seemingly highly alpha-helical. The aggregates formed at substantially different rates (apoE4>apoE3>apoE2) and were significantly more toxic to cultured neuronal cells than the tetramer. Since the three isoforms have large differences in conformational stability that can influence aggregation and amyloid pathways, we tested the effects of mutations that increased or decreased stability. Decreasing the conformational stability of the amino-terminal domain of apoE increased aggregation rates and vice versa. Our findings provide a new perspective for an isoform-specific pathogenic role for apoE aggregation in which differences in the conformational stability of the amino-terminal domain mediate neurodegeneration. 相似文献
An understanding of the time course and correlation with injury of heat shock proteins (HSPs) released during brain and/or spinal cord cellular stress (ischemia) is critical in understanding the role of the HSPs in cellular survival, and may provide a clinically useful biomarker of severe cellular stress. We have analyzed the levels of HSPs in the cerebrospinal fluid (CSF) from patients who are undergoing thoracic aneurysm repair. Blood and CSF samples were collected at regular intervals, and CSF was analyzed by enzyme-linked immunosorbent assay for HSP70 and HSP27. These results were correlated with intraoperative somatosensory-evoked potentials measurements and postoperative paralysis. We find that the levels of these proteins in many patients are elevated and that the degree of elevation correlates with the risk of permanent paralysis. We hypothesize that sequential measurement intraoperatively of the levels of the heat shock proteins HSP70 and HSP27 in the CSF can predict those patients who are at greatest risk for paralysis during thoracic aneurysm surgery and will allow us to develop means of preventing or attenuating this severe and often fatal complication. 相似文献
Introduction: Major Depressive Disorder (MDD) is the leading cause of global disability, and an increasing body of literature suggests different cerebrospinal fluid (CSF) proteins as biomarkers of MDD. The aim of this review is to summarize the suggested CSF biomarkers and to analyze the MDD proteomics studies of CSF and brain tissues for promising biomarker candidates.
Areas covered: The review includes the human studies found by a PubMed search using the following terms: ‘depression cerebrospinal fluid biomarker’, ‘major depression biomarker CSF’, ‘depression CSF biomarker’, ‘proteomics depression’, ‘proteomics biomarkers in depression’, ‘proteomics CSF biomarker in depression’, and ‘major depressive disorder CSF’. The literature analysis highlights promising biomarker candidates and demonstrates conflicting results on others. It reveals 42 differentially regulated proteins in MDD that were identified in more than one proteomics study. It discusses the diagnostic potential of the biomarker candidates and their association with the suggested pathologies.
Expert commentary: One ultimate goal of finding biomarkers for MDD is to improve the diagnostic accuracy to achieve better treatment outcomes; due to the heterogeneous nature of MDD, using bio-signatures could be a good strategy to differentiate MDD from other neuropsychiatric disorders. Notably, further validation studies of the suggested biomarkers are still needed. 相似文献
Glycosylation consists in the covalent linkage of a carbohydrate structure to membrane bound and secreted glycoconjugates. It is a common post-translational modification that serves multiple functions in cell differentiation, signaling and intercellular communication. Unlike DNA/RNA/protein, the addition of complex carbohydrates is not-template driven and it is conceivable that both genetics and environmental factors might interact to influence glycosylation machinery in several pathological processes. Over the last few decades, the recognition of Congenital Disorders of Glycosylation (CDG) as an increasing number of genetic diseases of glycosylation with almost constant nervous system involvement, dramatically illustrated the consequences of abnormal glycosylation as improper CNS development and function. In addition, CDG recognition contributed to postulate that aberrant glycosylation processes might play a role in multifactorial, complex CNS diseases. On this context, CNS glycomics explores the effects of possible aberrant glycosylation to identify potential glyco-biomarkers useful for the diagnosis and ultimately for potential intervention strategies in neurological diseases. Up to date, CNS glycomics is an emerging, still uncharted area because of the specificity of CNS glycosylation, the complexity of the neurological disorders and for the inaccessibility and invasiveness of disease relevant samples. Here we review current knowledge on clinical glycomics of nervous system diseases, starting with CDG to include those pediatric and adulthood neuropsychiatric diseases where some evidences suggest that multifactor determinants converge to dysregulate glycosylation. Conventional and mass spectrometry-based high throughput technology for glyco-biomarker detection in CNS diseases is reported. 相似文献
Techniques are described which have enabled the production and characterisation of monoclonal antibodies to myelin basic protein. These are shown by enzyme immunoassay to react with six different epitopes. Two of these are to peptide 82–91, a region claimed to be present in the spinal fluid of patients with demyelinating disease. One of these, an IgG2a, is shown to react only with peptides in which the 91–92 phe-phe bond has broken. The other, an IgM, also reacts with whole myelin basic protein. The IgG2a antibody is shown to have an affinity suitable for use in immunoassay of peptide 82–91. The enzyme immunoassay procedures described help to minimise the work load involved in the preparation and characterisation of monoclonal antibodies to this protein. 相似文献
Summary Free GABA levels were measured in the cerebrospinal fluid (CSF) of 74 neurological patients suffering from cerebral cysticercosis (n = 9), Parkinson's disease (n = 5), multiple sclerosis (n = 6), epilepsy (n = 24), meningeal tuberculosis (n = 6), viral encephalitis (n = 3), cerebrovascular disease (n = 8) and several kinds of dystonia (n = 5). A statistical significant four-fold elevation in free GABA levels was found in patients with cerebral cysticercosis. A non statistical significant two-fold increase in free GABA levels was also encountered in the CSF of patients affected by cerebrovascular disease and viral encephalitis. No changes in CSF free GABA levels were found in patients suffering from any of the other disorders. It is suggested that free GABA levels may be elevated in the CSF of patients suffering from neurological diseases which course with inflammation and tissular necrosis such as cerebral cysticercosis. Much work is needed however to establishd whether CSF free GABA levels can be used as a diagnostic tool in at least some type of these patients. 相似文献
Abstract: In adult New Zealand white rabbits, the effects of food deprivation and of massive elevations of plasma uridine or thymidine concentrations on CSF and plasma nucleoside and oxypurine concentrations were studied. Nucleoside and oxypurine levels were determined by high performance liquid chromatography using unequivocal methods of compound identification. After 48 and 96 h of food deprivation, the concentrations of uridine, cytidine, inosine, thymidine, deoxycytidine, deoxyuridine, hypoxanthine, xanthine, and uric acid in CSF and plasma were not different than in controls, except at 96 h, when the plasma uridine concentration was 35% lower (p < 0.05). After elevation of the plasma and CSF thymidine concentrations to ∼200 and 100 μM, respectively, with intravenous thymidine for 5 h, there was a large increase in CSF and plasma thymine to ∼100 μM and a smaller increase in plasma and CSF deoxyuridine concentrations. After elevation of the plasma and CSF uridine concentrations to 0.6 and 0.2 mM, respectively, there was a large increase in CSF and plasma uracil and a smaller increase in plasma and CSF deoxyuridine concentrations. Elevated plasma concentration of thymidine and uridine significantly decreased the CSF to plasma ratios of deoxyuridine and thymidine; however, only elevated plasma uridine concentrations decreased the CSF to plasma ratio of uridine. These results document the powerful homeostatic mechanisms that regulate the concentrations of the principal nucleosides and oxypurine bases in CSF. 相似文献
Intramuscular injection of synthetic VIP (200 micrograms) resulted in a rapid increase in plasma prolactin (PRL) concentrations in normal women, which was accompanied by the 4- to 7-fold increase in plasma VIP levels. Mean (+/- SE) peak values of plasma PRL obtained 15 min after the injection of VIP were higher than those of saline control (28.1 +/- 6.7 ng/ml vs. 11.4 +/- 1.6 ng/ml, p less than 0.05). Plasma growth hormone (GH) and cortisol levels were not affected by VIP in normal subjects. VIP injection raised plasma PRL levels (greater than 120% of the basal value) in all of 5 patients with prolactinoma. In 3 of 8 acromegalic patients, plasma GH was increased (greater than 150% of the basal value) by VIP injection. In the in vitro experiments, VIP (10(-8), 10(-7) and 10(-6) M) stimulated PRL release in a dose-related manner from the superfused pituitary adenoma cells obtained from two patients with prolactinoma. VIP-induced GH release from the superfused pituitary adenoma cells was also shown in 5 out of 6 acromegalic patients. VIP concentrations in the CSF were increased in most patients with hyperprolactinemia and a few cases with acromegaly. These findings indicate that VIP may play a role in regulating PRL secretion in man and may affect GH secretion from pituitary adenoma in acromegaly. 相似文献