RESUMEN
INTRODUCTION: Evidence-based information about cerebrospinal fluid (CSF) levels of biomarkers in patients with amyotrophic lateral sclerosis (ALS) is limited. METHODS: Vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2), optineurin (OPTN), monocyte chemoattractant protein-1 (MCP-1), angiogenin (ANG), and TAR DNA-binding protein (TDP-43) were quantified by enzyme-linked immunoassay in the CSF of 54 patients with sporadic ALS and 32 controls in a case-control study design. RESULTS: CSF levels of VEGF (P = .014) and ANG (P = .009) were decreased, whereas VEGFR2 was higher (P = .002) in patients with ALS than in controls. TDP-43 positively correlated with MCP-1 (P = .003), VEGF (P < .001), and VEGFR2 (P < .001) in patients with ALS. DISCUSSION: Our findings suggest possible utility of VEGF, VEGFR2, and ANG as biomarkers for use in ALS treatment trials.
Asunto(s)
Esclerosis Amiotrófica Lateral/diagnóstico , Proteínas de Ciclo Celular/líquido cefalorraquídeo , Quimiocina CCL2/líquido cefalorraquídeo , Proteínas de Unión al ADN/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Ribonucleasa Pancreática/líquido cefalorraquídeo , Factor A de Crecimiento Endotelial Vascular/líquido cefalorraquídeo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/líquido cefalorraquídeo , Adulto , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Femenino , Humanos , India , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: ß-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity determines the rate of APP cleavage and is therefore the main driver of amyloid ß production, which is a pathological hallmark of Alzheimer's disease (AD). METHODS: The present study explored the correlation between BACE1 activity and cerebrospinal fluid (CSF) markers of APP metabolism and axonal degeneration in 63 patients with mild AD and 12 healthy control subjects. RESULTS: In the AD group, positive correlations between BACE1 activity and soluble APP ß, the APP sorting receptor sortilin-related receptor with A-type repeats (also known as SorLA or LR11), and tau were detected. BACE1 activity was not associated with amyloid ß1-42 or soluble APP α concentrations in the AD group, and no associations between BACE1 activity and any of the protein concentrations were found in the control group. CONCLUSION: Our results confirm the relevance of BACE1 and sortilin-related receptor with A-type repeats within the amyloid cascade and also provide a further piece of evidence for the link between amyloid and tau pathology in AD.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Secretasas de la Proteína Precursora del Amiloide/líquido cefalorraquídeo , Ácido Aspártico Endopeptidasas/líquido cefalorraquídeo , Proteínas Relacionadas con Receptor de LDL/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Adulto , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/metabolismo , Biomarcadores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Psicometría , Degeneración RetrógradaRESUMEN
LR11 (also called SorLA or SORL1), a member of the LDL receptor family, was originally discovered in 1996 from genes specifically expressed in the intimal smooth muscle cells of atherosclerotic plaques. The soluble form of LR11 (sLR11) as well as the membrane-bound form plays a key role in the phenotype conversion of medial smooth muscle cells into intimal smooth muscle cells through the activation of urokinase receptor/integrin-mediated intracellular pathways. The levels of sLR11 in serum or CSF are increased in patients with atherosclerotic diseases, Alzheimer's disease or malignant diseases including acute leukemias. The recently developed ELISA system using two specific antibodies against LR11 made it possible to measure sLR11 quantitatively and stably for many samples. Thus, a novel clinical examination is expected to detect the pathological immature cells important for the pathophysiology of the above diseases. The soluble receptor-based clinical approach, together with basic studies about the structure-function relationship, may shed light on the development of novel target therapy against pathological immature cells in the science fields of so far independently categorized diseases.
Asunto(s)
Proteínas Relacionadas con Receptor de LDL/sangre , Proteínas Relacionadas con Receptor de LDL/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/sangre , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Receptores de LDL/análisis , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Biomarcadores/análisis , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/patología , Humanos , Proteínas Relacionadas con Receptor de LDL/metabolismo , Leucemia/metabolismo , Leucemia/patología , Proteínas de Transporte de Membrana/metabolismo , Receptores de LDL/metabolismo , SolubilidadRESUMEN
The neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) is involved in amyloidogenesis, and the SORL1 gene is a major risk factor for Alzheimer's disease (AD). We investigated AD-related CSF biomarkers for associations with SORL1 genetic variants in 105 German patients with mild cognitive impairment (MCI) and AD. The homozygous CC-allele of single nucleotide polymorphism (SNP) 4 was associated with increased Tau concentrations in AD, and the minor alleles of SNP8, SNP9, and SNP10 and the haplotype CGT of these SNPs were associated with increased SORL1 concentrations in MCI. SNP22 and SNP23, and the haplotypes TCT of SNP19-21-23, and TTC of SNP22-23-24 were correlated with decreased Ab42 levels in AD. These results strengthen the functional role of SORL1 in AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/genética , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Estudios de Casos y Controles , Disfunción Cognitiva/líquido cefalorraquídeo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Proteínas Relacionadas con Receptor de LDL/líquido cefalorraquídeo , Masculino , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple , Proteínas tau/líquido cefalorraquídeoRESUMEN
Recently, light has been shed on possible interrelations between the two most important pathological hallmarks of Alzheimer's disease (AD): the amyloid cascade and axonal degeneration. In this study, we investigated associations between sßAPPß, a product of the cleavage of the amyloid-ß protein precursor (AßPP) by ß-secretase, amyloid-ß 1-42 (Aß42), soluble SORL1 (also called LR11 or SORLA), a receptor that is involved in AßPP processing, and the marker of axonal degeneration tau in the cerebrospinal fluid (CSF) of 76 patients with mild cognitive impairment (MCI), 61 patients with AD, and 17 patients with frontotemporal dementia, which neuropathologically is not related to the amyloid pathology. In the AD group, significant associations between sAßPPß, tau (p < 0.001), and soluble SORL1 (p < 0.001) were detected according to linear regression models. In patients with MCI, sAßPPß correlated significantly with tau (p < 0.001) and soluble SORL1 (p = 0.003). In the FTD group, only SORL1 (p = 0.011) was associated with sAßPPß and not tau. Aß42 was found to be significantly related to tau levels in CSF in the MCI group (p < 0.001) and they tended to be associated in the AD group (p = 0.05). Our results provide further evidence for a link between the two facets of AD pathology, which is likely to be mediated by the binding of Aß oligomers to specifically targeted neurons, resulting in stimulating tau hyperphosphorylation and neurodegeneration.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Proteínas Relacionadas con Receptor de LDL/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/complicaciones , Análisis de Varianza , Distribución de Chi-Cuadrado , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Demencia Frontotemporal/líquido cefalorraquídeo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A variable poly-T polymorphism in the TOMM40 gene, which is in linkage disequilibrium with APOE, was recently implicated with increased risk and earlier onset age for late-onset Alzheimer's disease in APOE ε3 carriers. To elucidate potential neurobiological mechanisms underlying this association, we compared the effect of TOMM40 poly-T variants to the effect of APOE, an established LOAD-risk modulator, on cerebrospinal fluid (CSF) amyloid beta (Aß) and tau levels, in cognitively intact elderly subjects. APOE ε4 carriers showed significant reductions in Aß 1-42 levels compared to non-ε4 carriers, but no differences were detected across TOMM40 variants. Neither Aß 1-40 nor tau levels were affected by APOE or TOMM40.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Humanos , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Proteínas del Complejo de Importación de Proteínas Precursoras MitocondrialesRESUMEN
OBJECTIVES: CSF levels of Aß1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aß1-42, t-tau, p-tau181p, p-tau181p/Aß1-42, and t-tau/Aß1-42). METHODS: A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p<0.01 (uncorrected p<3.10×10(-8)) and secondarily examined SNPs with uncorrected p values less than 10(-5) to identify potential candidates. RESULTS: Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates. CONCLUSIONS: In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/genética , Treonina/metabolismo , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Antígenos de Neoplasias/líquido cefalorraquídeo , Antígenos de Neoplasias/genética , Apolipoproteínas E/genética , Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Estudios de Cohortes , Diagnóstico por Imagen , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Fosforilación , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Recent genetic and pathological studies have suggested that a lipoprotein receptor, LR11, is intricately implicated in the pathogenesis of Alzheimer disease (AD). We have recently established a novel sandwich ELISA, which enabled the sensitive quantification of a soluble LR11 (sLR11). By this ELISA, we attempted to determine the difference in the levels of CSF sLR11 in AD patients. METHODS: We examined CSF from 29 AD patients, 20 frontotemporal lobar degeneration patients and 27 age-matched control subjects. The CSF sLR11 level as well as the levels of tau and beta-amyloid42 (Abeta42) were determined by sandwich ELISA. RESULTS: The CSF tau level and tau/Abeta42 ratio were significantly increased (p < 0.01) in the AD patients. The CSF sLR11 level in the AD patients was significantly higher (p < 0.01) than that of the frontotemporal lobar degeneration patients and the controls. The APOE-epsilon4-positive AD patients have higher sLR11 levels than the APOE-epsilon4-negative patients (p < 0.01). CONCLUSIONS: These results suggest that the quantification of CSF sLR11 may serve as a biomarker of AD, although the diagnostic value for individual patients is limited. An elevated CSF sLR11 level in AD patients may be relevant to AD pathogenesis.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Proteínas Relacionadas con Receptor de LDL/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores , Ensayo de Inmunoadsorción Enzimática , Femenino , Degeneración Lobar Frontotemporal/líquido cefalorraquídeo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteínas tau/líquido cefalorraquídeoRESUMEN
In the last 40 years, especially with the application of new neurochemical and molecular biological techniques, there has been explosive progress in understanding how certain ligands and drugs are transported across the blood-brain barrier and choroid plexus out of brain and CSF. In the CNS, there are several separate efflux transporters with very broad specificity that are responsible for much of the efflux transport. This review focuses on three such transporters: organic acid transporter-3, peptide transporter-2 and P-glycoprotein for which there is substantial new information including 'knockout' models in mice and, in one case, dogs. Moreover, the structural biology and transport mechanism of P-glycoprotein at 3.8 angstroms is described. The overall objective is to show how this new knowledge provides a more thorough understanding (e.g., of molecular mechanisms) of efflux transport and in several cases leads to clinically relevant information that allows better treatment of certain CNS disorders (e.g., meningitis and brain cancer).
Asunto(s)
Encéfalo/metabolismo , Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/fisiología , Encéfalo/fisiología , Enfermedades del Sistema Nervioso Central/metabolismo , Humanos , Proteínas de Transporte de Membrana/fisiología , Transporte de Proteínas/fisiología , Factores de TiempoRESUMEN
BACKGROUND: Vascular smooth muscle cells (SMCs) migrate from the arterial media to the intima in the progression of atherosclerosis, and dysfunction of SMCs leads to enhanced atherogenesis. A soluble form of the LDL receptor relative with 11 ligand-binding repeats (sLR11) is produced by the intimal SMCs, and the circulating concentrations of sLR11 likely reflect the pathophysiological condition of intimal SMCs. Furthermore, polymorphism of the LR11 gene has been found to be related to the onset of Alzheimer disease. This study describes the development of a sandwich immunoassay for quantifying sLR11 in human serum and cerebrospinal fluid. METHODS: We used synthetic peptides or DNA immunization to produce monoclonal antibodies (MAbs) A2-2-3, M3, and R14 against different epitopes of LR11. RESULTS: sLR11 was immunologically identified as a 250-kDa protein in human serum and cerebrospinal fluid by SDS-PAGE separation, and was purified from serum by use of a receptor-associated protein and MAb M3. An immunoassay for quantification of sLR11 with a working range of 0.25-4.0 microg/L was developed using the combination of MAbs M3 and R14. Treatment of serum with 5.25% n-nonanoyl-N-methyl-d-glucamine reduced the matrix effects of serum on the absorbance detection in the ELISA system. The linear dynamic range of the ELISA spanned the variation of circulating sLR11 concentrations in individuals with atherosclerosis. CONCLUSIONS: A sandwich ELISA was established for quantifying sLR11 in serum and cerebrospinal fluid. This technique provides a novel means for assessing the pathophysiology of atherosclerosis, and possibly neurodegenerative diseases.
Asunto(s)
Aterosclerosis/sangre , Aterosclerosis/líquido cefalorraquídeo , Proteínas Relacionadas con Receptor de LDL/sangre , Proteínas Relacionadas con Receptor de LDL/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/sangre , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Animales , Anticuerpos Monoclonales , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Línea Celular , Cromatografía en Gel , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Proteínas Relacionadas con Receptor de LDL/inmunología , Masculino , Proteínas de Transporte de Membrana/inmunología , Conejos , Valores de ReferenciaRESUMEN
BACKGROUND: The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces beta-amyloid precursor protein trafficking to secretases, notably BACE1 that generates beta-amyloid, the principal component of senile plaques in Alzheimer disease (AD). LR11 protein is reduced in patients with late-onset AD, and LR11 polymorphisms have been associated with late-onset AD. OBJECTIVE: T o detect soluble LR11 and APP in cerebrospinal fluid (CSF) from patients with AD and control subjects, as (like beta-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells. DESIGN: Case-control study. SETTING: Academic research. PARTICIPANTS: Patients with AD and control subjects. MAIN OUTCOME MEASURES: We evaluated CSF LR11, beta-amyloid precursor protein, and apolipoprotein E levels by Western blot in lumbar and postmortem CSF samples. RESULTS: LR11 levels were detectable and stable during 6 months in the CSF of patients with AD. LR11 levels were significantly reduced in lumbar samples from patients with mild to moderate probable AD, as well as in ventricular CSF from patients with autopsy-confirmed AD (predominantly Braak stage III-IV). Bivariate analysis with beta-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble beta-amyloid precursor protein but not apolipoprotein E levels. CONCLUSION: Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote beta-amyloid production or as an index of therapeutic response in late-onset AD.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Encéfalo/metabolismo , Proteínas Relacionadas con Receptor de LDL/líquido cefalorraquídeo , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Apolipoproteínas E/líquido cefalorraquídeo , Western Blotting , Encéfalo/patología , Estudios de Casos y Controles , Línea Celular , Regulación de la Expresión Génica/genética , Humanos , Ovillos Neurofibrilares/patología , Fragmentos de Péptidos/líquido cefalorraquídeo , Placa Amiloide/patología , Valor Predictivo de las Pruebas , Valores de ReferenciaRESUMEN
BACKGROUND: The pathogenesis of idiopathic normal pressure hydrocephalus (INPH) is unknown, and the syndrome of INPH remains a diagnostic and therapeutic challenge. The present study investigated the disease-specific proteins that aid in the diagnosis and treatment of INPH and thus to study their role in the disease process. METHODS: A comparative proteomic analysis was used for clinical screening of cerebrospinal fluid (CSF) proteins in 15 patients with INPH and compared with 12 normal subjects. Furthermore, enzyme linked immunosorbent assay (ELISA) was performed for comparison with CSF proteins between individual INPH patients and controls. RESULTS: Seven proteins and their isoforms, including leucine-rich alpha-2-glycoprotein (LRG), alpha1-antichymotrypsin, apolipoprotein D, apolipoprotein J, haptoglobin alpha1, serum albumin, and alpha-1-microglobulin/bikunin precursor showed significant changes in CSF of INPH patients compared with controls by proteomic analysis. And significant higher CSF levels of LRG in INPH patients compared with controls were found by ELISA. CONCLUSIONS: These results indicate that there are significant differences in the expression of certain proteins in the CSF of patients with INPH and normal subjects. In particular, the CSF level assay of LRG suggests that LRG is a specific biomarker for INPH and has potential use in the diagnosis and indication for CSF shunting.