Carlos Fernández-Viadero

Case-control study and meta-analysis of low density lipoprotein receptor-related protein gene exon 3 polymorphism in Alzheimer's disease

The low density lipoprotein receptor-related protein (LRP) may influence both the clearance and the production of beta-amyloid peptide and thus plays a role in Alzheimers disease (AD) pathogenesis. Previous studies, although inconsistent, have suggested that the LRP exon 3 CC genotype contributes to the risk of AD. A case-control study utilizing a clinically well-defined group of 305 sporadic AD patients and 304 control subjects was performed to test this association in an ethnically homogeneous population from Spain. In the current study, the LRP CC genotype was not over-represented in AD patients compared to non-demented controls. A meta-analysis of previous studies revealed a weak correlation of LRP CC genotype with AD (odds ratio of 1.35, P=0.01).

Effects of melatonin on the proliferation and differentiation of human neuroblastoma cells in culture

Since melatonin has direct inhibitory effects on some tumor cells in vitro, the aim of the present work was to study whether the growth and structural characteristics of the human neuroblastoma cell line SK-N-SH in vitro are influenced by this indoleamine. Concentrations of melatonin of 10(-9) and 10(-11) M significantly inhibited (P < 0.05) cell proliferation. Subphysiological (10(-13) M) or supraphysiological (10(-7) and 10(-5) M) concentrations of melatonin lacked this effect. After 8 days of exposure to melatonin (10(-9) M), cells showed significantly smaller cell and nuclear sizes than control cells. Melatonin-treated cells presented greater neurite outgrowth than control cells. These results support the hypothesis that melatonin, at physiological concentrations, exerts a direct antiproliferative effect on SK-N-SH cells, promoting the differentiation of neuroblastoma cells.

Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer's disease risk.

Excessive release of proinflammatory cytokines by activated microglia surrounding senile plaques might contribute to the neurodegeneration associated with Alzheimer’s disease (AD). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear protein recently implicated in the initial inflammatory response by modulating expression of inflammation-related genes, like interleukin 1 (IL-1). As PARP-1 overactivity has been shown in the AD brain, we tested the hypothesis that the PARP-1 –410 and –1672 polymorphisms would predispose people to AD due to overexpression of the PARP-1 gene, independently or in concert with the proinflammatory IL-1A –889 polymorphism. So, we performed a case-control study in 263 Spanish AD patients and 293 healthy controls. PARP-1 –410 and PARP-1 –1672 haplotypes were associated with an increased risk for AD (global haplotype association p value = 0.019), and, in addition, PARP-1 haplotypes increased the risk of AD by interaction with the IL-1A –889 allele 2.

CD14 receptor polymorphism and Alzheimer's disease risk

Activation of microglial cells is involved in the inflammatory component of Alzheimers disease (AD), and it may be triggered by infectious pathogens. CD14, a receptor upregulated in activated microglia, plays a central role in innate immunity through recognition of bacterial lipopolysaccharide and initiation of inflammatory response. A polymorphism in the promoter region (-260) of the CD14 receptor has been found to be related to increased risk of bacterial infections and inflammatory diseases such as atherosclerosis. In a case-control study utilizing a clinically well-defined group of 310 sporadic AD patients and 310 control subjects, we investigated whether the CD14 (-260) polymorphism might be responsible for susceptibility to AD, and we also examined the combined gene effects between CD14 and APOE and several other proinflammatory cytokine genes. The current study does not demonstrate an association between CD14 (-260) polymorphism and AD, neither through an independent effect nor through interaction with APOE epsilon4 allele or interleukin (IL)-1A, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and intercellular adhesion molecule-1 polymorphisms.

The myeloperoxidase gene in Alzheimer's disease: a case-control study and meta-analysis.

Myeloperoxidase (MPO) presence has been demonstrated in microglia associated with senile plaques, and contributes to Alzheimers disease (AD) pathology through oxidation-induced damage. Recently, a functional biallelic (G/A) polymorphism in the promotor region (-463) of the MPO gene has been associated with susceptibility to AD, but the reports of this association have been inconsistent. A case-control study utilizing a clinically well-defined group of 315 sporadic AD patients and 327 control subjects was performed to test this association. The current study does not demonstrate any significant difference in MPO genotype or allele frequencies between AD patients and controls. A meta-analysis of all studies available gave a non-significant (P=0.83) odds ratio of 1.02 for the MPO GG genotype. Our study in the Spanish population as well as the meta-analysis argue against the hypothesis that the MPO gene is causally related to AD.

Age-Dependent Association between the Q7R Polymorphism in the Saitohin Gene and Sporadic Alzheimer’s Disease

A vigorous controversy exists over whether tau tangles or amyloid-β plaques are the primary cause of neurodegeneration in Alzheimer’s disease (AD), and it is not well established whether genetic variation in tau is associated with AD. A recently identified novel protein, named Saitohin (STH), shares tissue expression pattern with tau, and preliminary evidence in a North American population indicates that a polymorphism at codon 7 (Q7R) of the STH gene is a predisposing factor for sporadic AD. A case-control study utilizing a clinically well-defined group of 315 sporadic AD patients and 307 control subjects was performed to test this association. The current study reveals that increased risk of AD associated with the STH RR genotype (OR 2.17, p = 0.04) is limited to late-onset (after the age of 72 years) AD cases.

Interaction between interleukin–6 and intercellular adhesion molecule–1 genes and Alzheimer’s disease risk

Sirs: The immune system contributes to the neurodegeneration associated with Alzheimer’s disease (AD), and there is evidence that βamyloid is a potent activator of microglial cells (local immunocompetent cells) through upregulated expression of adhesion molecules, specifically intercellular adhesion molecule-1 (ICAM-1) [17]. Activated microglia release proinflammatory cytokines, such as interleukin-6 (IL-6) [8], which further stimulate and activate ICAM-1 expression, thus setting up a vicious cycle of perpetuated microglial activation. The functional effects of IL-6 are mediated through a specific receptor complex made up of a ligand glycoprotein (IL-6R) and a signal transducing glycoprotein (gp130); the soluble form of IL-6R (sIL-6R) is able to bind to IL-6 and activates the gp130 transducing chain [3]. Genetic differences between individuals in the regulation of ICAM1 and IL-6 production may be critical with respect to the final outcome of chronic inflammatory response in the AD brain. A polymorphism (E469K) occurs in exon 6 of the ICAM-1 gene and results in a change from glutamic acid (E) to lysine (K) in Ig-like domain 5 of ICAM-1, and this domain is of crucial importance for the activity of the ICAM-1 protein [15]; thus, the K allele should be protective against inflammation. A biallelic (G/C) polymorphism in the promoter region [–174] of the IL-6 gene regulates transcription rate and blood level of this cytokine, and the C allele is associated with reduced IL-6 gene expression and also reduced levels of plasma IL-6 [7]. Plasma and cerebrospinal fluid levels of sIL-6R are significantly increased in AD patients and the magnitude of increase is determined by this IL-6 [–174] polymorphism [3]. Recently, both ICAM-1 (E469K) [10, 12, 13] and IL-6 [–174] [1–6, 9, 11, 14] polymorphisms were found to be associated with susceptibility for AD, but the findings have been inconsistent. Therefore, we investigated the interaction between ICAM-1 (E469K) and IL-6 [–174] polymorphisms in determining the risk of AD, and we performed meta-analyses for both polymorphisms using all published findings of case-control studies until March 2004. The study included 234 AD patients (67 % women; mean age at the time of study 75.1 years; SD 8.3; range 50–98; mean age at onset 71.7 years; SD 8.3; range 48–95) who met NINCDS/ADRDA criteria for probable AD. All AD cases were defined as sporadic because their family history did not mention any first-degree relative with dementia; this information was obtained by direct interviews with relatives. Control subjects consisted of 197 unrelated individuals (71 % women; mean age 79.8 years; SD 7.9; range 63–98) who had complete neurological and medical examinations establishing that they were free of significant illness and all had Mini Mental State Examination scores of 28 or more. Control subjects were randomly selected from a nursing home. The AD and control samples were Caucasians originating from a homogeneous population in a limited geographical area in Northern Spain. The IL-6 [–174] and ICAM-1 (E469K) polymorphisms were determined as described previously [4, 13]. The study was approved by the ethical committee of the University Hospital “Marqués de Valdecilla”. Association between dichotomous variables was analysed with odds ratio, and 95 % confidence intervals were estimated by the Cornfield method or the Fisher exact method. P-values were estimated by chi-square or Fisher exact tests. Interrelations were analysed by stratification. For meta-analyses, point estimates of risk for each study were tested for homogeneity by the χ2 (Wald) test. As this test is rather conservative, a P value lower than 0.10 was considered as significant and indicated heterogeneity of the samples between studies. When significant heterogeneity was present, a random-effects model was used to calculate a pooled weighted point estimate of risk, controlling for both within-study and betweenstudy variability. Pooled odds ratios in the meta-analyses were performed weighing odds ratios by the inverse of their variance (Der Simonian-Laird method). The distributions of the IL-6 (P = 0.484) and ICAM-1 (P = 0.473) genotypes were in Hardy-Weinberg equilibrium. The presence of the IL-6 C/C genotype conferred a significant decrease in the risk for the disease (OR 0.55, 95 % CI 0.30–0.99, P = 0.034), and the presence of the ICAM-1 K/K genotype was not associated with AD (OR 1.08, 95 % CI 0.69–1.70, P = 0.732). Splitting the groups according to their ICAM-1 genotype showed that the decreased risk for AD, in carriers of LETTER TO THE EDITORS

Neurons co-localizing calretinin immunoreactivity and reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity in the hippocampus and dentate gyrus of the rat

Co-localization of calretinin immunoreactivity and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity was studied in the rat hippocampus and dentate gyrus. Neurons co-expressing both markers (CR/NADPH-d) were observed throughout the hippocampus and dentate gyrus. However, they were more abundant in the stratum pyramidale and radiatum of CA3, stratum pyramidale of CA1, and in the juxtagranular zone of the hilus. The NADPH-d activity appeared in 37% of the calretinin immunoreactive neurons in CA3, 42% in CA1, and 36% in the dentate gyrus, whereas calretinin immunoreactivity occurred in 41% of the NADPH-d positive neurons in the hippocampus, and 16% in the dentate gyrus. The morphology and location of the double marked cells could not be used as a characteristic of the co-localizing neurons. The heavily stained NADPH-d neurons occurring mainly in CA1 do not show calretinin immunoreactivity. NADPH-d fiber swellings could be observed in close apposition to calretinin immunoreactive neurons and dendrites, suggesting synaptic contacts. It has been reported that calretinin immunoreactivity and NADPH-d activity co-localize infrequently in other areas such as the neocortex, striatum, hypothalamus and tegmental nucleus. The relatively high proportion of double marked cells found in the hippocampus and dentate gyrus could be indicative of the importance of the CR/NADPH-d interneurons in the circuitries of these areas.

The influence of age on supraoptic nucleus neurons of the rat: Morphometric and morphologic changes

Neurosecretory neurons (NSNs) of the supraoptic nucleus of 2-year-old rats presented significantly greater nuclear volumes and nuclear perimeters than those of 3-month-old animals. In aged NSNs, membranous bodies (MBs) were observed in the cytoplasm and the cell nucleus. The possible origin and function of these MBs are discussed.

The chemokine receptor CCR5-Δ32 gene mutation is not protective against Alzheimer’s disease

Chronic local inflammatory reaction involving reactive microglia is one of the major pathological events in Alzheimers disease (AD). There is growing evidence that the chemokine receptor CCR5 is up-regulated in AD brain and plays a role in the recruitment and accumulation of microglia in senile plaques. A 32-base pair deletion in the CCR5 gene (CCR5-Delta32 mutant allele) confers resistance to HIV-1 infection by preventing expression of the receptor on the cell surface. Several other reports have shown a similar protective effect of CCR5-Delta32 mutation towards certain chronic inflammatory diseases. Given the potential importance of CCR5 in brain inflammation, we hypothesized that individuals carrying the CCR5-Delta32 allele would show a reduced risk of AD. So, we performed a case-control study in 376 Spanish AD patients and 369 healthy controls. The frequency of the CCR5-Delta32 allele in our AD sample was 7.8%, not significantly different from our control sample group (5.8%). The present study indicates that the CCR5-Delta32 allele is not a preventive factor for AD.