Ana Frank

Increased cerebrospinal fluid Fas (Apo-1) levels in Alzheimer’s disease: Relationship with IL-6 concentrations

Increasing lines of evidence suggest a role of apoptosis in the neurodegeneration associated with Alzheimers disease, in which it has been implicated in increasing the expression of p53 and Fas. On the other hand, inflammatory cytokines have also been implicated as important factors in the progression of neuronal damage in this disease. In an attempt to investigate the possible in vivo relationship between programmed cell death and the inflammatory response in patients with dementia of the Alzheimer type (DAT), we measured the levels of soluble Fas, interleukin-1beta (IL-lbeta) and IL-6 in cerebrospinal fluid (CSF) from ten DAT patients and ten age-matched controls. Our results show a significant increase in IL-6 and soluble Fas concentrations in the CSF of DAT patients compared with those from nondemented controls. Moreover, linear regression analysis demonstrated a significant correlation (r=0.703; P<0.05) between soluble Fas and IL-6 levels in the CSF in DAT patients. These results suggest that Fas is implicated in the inflammatory response observed in Alzheimers brains.

Increased cerebrospinal fluid cAMP levels in Alzheimer's disease

Since increasing evidence suggests that upregulation of the cAMP-second messenger system may be implicated in Alzheimers disease neurodegeneration, we have compared the cAMP and cGMP levels in cerebrospinal fluid (CSF) from patients with dementia of the Alzheimer type (DAT, n=10) with those from nondemented age-matched controls (n=10). Our results show that cAMP levels, but not cGMP, are significantly (p<0.01) elevated in CSF from patients with DAT compared to those from nondemented controls. Moreover, a linear regression analysis demonstrated a significant correlation (r=0.62; p<0.01) between cAMP and tau protein levels in CSF when controls and patients with DAT were studied together. These results suggest that upregulation of cAMP-signaling pathway is implicated in Alzheimers disease physiopathology.

Relationship of interleukin-1β and β2-microglobulin with neuropeptides in cerebrospinal fluid of patients with dementia of the Alzheimer type

Abstract We studied interleukin-1β (IL-1β), β 2 -microglobulin ( β 2 -m, β-endorphin, substance P, neuropeptide Y and somatostatin concentrations in the cerebrospinal fluid of 13 patients with dementia of the Alzheimer type (DAT), 13 patients with multi-infarct dementia (MID) and 15 age-matched control subjects. Substance P was significantly lower in DAT than in controls ( P P P β 2 -m was higher in DAT than in controls ( P r = 0.79, P r = 0.75, P β 2 -m showed a negative correlation with IL-1β ( r = −0.73, P

IGF-I gene variability is associated with an increased risk for AD.

Insulin-like growth factor I (IGF-I), a neuroprotective factor with a wide spectrum of actions in the adult brain, is involved in the pathogenesis of Alzheimers disease (AD). Circulating levels of IGF-I change in AD patients and are implicated in the clearance of brain amyloid beta (Aβ) complexes. To investigate this hypothesis, we screened the IGF-I gene for various well known single nucleotide polymorphisms (SNPs) covering % of the gene variability in a population of 2352 individuals. Genetic analysis indicated different distribution of genotypes of 1 single nucleotide polymorphism, and 1 extended haplotype in the AD population compared with healthy control subjects. In particular, the frequency of rs972936 GG genotype was significantly greater in AD patients than in control subjects (63% vs. 55%). The rs972936 GG genotype was associated with an increased risk for disease, independently of apolipoprotein E genotype, and with enhanced circulating levels of IGF-I. These findings suggest that polymorphisms within the IGF-I gene could infer greater risk for AD through their effect on IGF-I levels, and confirm the physiological role IGF-I in the pathogenesis of AD.

Double stranded RNA activated EIF2 α kinase (EIF2AK2; PKR) is associated with Alzheimer's disease

Sporadic Alzheimers disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors (for example virus infections). To test this hypothesis, we are examining human genes relevant to herpes simplex virus type 1 (HSV-1) infection via genetic association studies in AD case–control samples. Recently, we found that a variant in TAP2, a major target used by HSV-1 to evade immune surveillance, is associated with AD. The present work analyses another gene involved in the host cell response to HSV-1, EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2; coding for PKR); PKR mediates the virus-induced shut-off of translation, and levels of activated PKR are high in the brains of AD patients. An EIF2AK2 SNP (rs2254958) located in the 5′-UTR region within an exonic splicing enhancer was found to be associated with AD. More specifically: the C allele was more commonly found in the patients and, compared to non-CC genotypes, the CC homozygotes showed earlier (around 3.3 years) onset of AD, especially in the absence of the APOE4 allele. These results further support the hypothesis that variants of human genes participating in HSV-1 infection modulate the susceptibility and/or clinical manifestations of AD.

A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease

Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimers disease (AD), is intimately linked to aging – the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking the situation in AD brains, are therefore of great interest. This paper reports that, in human neuronal cells, oxidative stress induced by the free radical‐generating xanthine/xanthine oxidase (X‐XOD) system leads to apoptotic cell death. Microarray analyses showed a potent activation of the cholesterol biosynthesis pathway following reductions in the cell cholesterol synthesis caused by the X‐XOD treatment; furthermore, the apoptosis was reduced by inhibiting 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) expression with an interfering RNA. The potential importance of this mechanism in AD was investigated by genetic association, and it was found that HMGCR, a key gene in cholesterol metabolism and among those most strongly upregulated, was associated with AD risk. In summary, this work presents a human cell model prepared to mimic the effect of oxidative stress in neurons that might be useful in clarifying the mechanism involved in free radical‐induced neurodegeneration. Gene expression analysis followed by genetic association studies indicates a possible link among oxidative stress, cholesterol metabolism and AD.

Plasma Aminothiol Compounds, but Not Serum Tumor Necrosis Factor Receptor II and Soluble Receptor for Advanced Glycation End Products, Are Related to the Cognitive Impairment in Alzheimer’s Disease and Mild Cognitive Impairment Patients

Increasing evidence indicates that factors such as oxidative stress, plasma homocysteine increase and glutathione depletion, elevated pro-inflammatory cytokines and advanced glycation end products can play a role in Alzheimer’s disease (AD) pathogenesis. The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in neurodegeneration, and a soluble isoform of RAGE (sRAGE) has the ability to prevent the adverse effects of RAGE signaling by acting as a decoy. Twenty-five patients with AD, 26 with mild cognitive impairment (MCI) and 44 age-matched control subjects were studied. All subjects were classified according to their clinical, cognitive and positron emission tomography study. Serum levels of sRAGE and TNF-α receptor II were not significantly different in AD or MCI patients compared to controls. Total plasma levels of glutathione and its metabolite cysteinglycine were decreased in AD and MCI patients compared to the control group. In addition, AD patients presented significantly increased plasma homocysteine compared to those in MCI patients and controls. We found significant positive correlations between sRAGE and glutathione, cysteinglycine and cysteine levels. Moreover, a significant negative correlation between the total score of cognitive impairment and homocysteine levels, and significant positive correlations with glutathione, cysteinglycine and cysteine levels were observed. These findings indicate that plasma aminothiol compounds are associated with AD and MCI patients and with their cognitive status.

A TAP2 genotype associated with Alzheimer's disease in APOE4 carriers

Sporadic Alzheimers disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors. Binding with the transporter associated with antigen processing (TAP) is thought to be the main way in which herpes simplex virus type 1 (HSV-1) evades immune surveillance. Several TAP gene polymorphisms were examined and a TAP2 SNP (rs241448) associated with AD found in two independent case-control samples, especially in carriers of the APOE4 allele. These findings are consistent with the hypothesis that human genetic variants facilitating the access of HSV-1 to the brain might result in susceptibility to AD.

Epistasis between intracellular cholesterol trafficking-related genes (NPC1 and ABCA1) and Alzheimer's disease risk

Aberrant cholesterol metabolism has been implicated in Alzheimers disease (AD). Recent findings have suggested an interaction of Niemann-Pick C1 (NPC1) and ATP-binding cassette transporter A1 (ABCA1) proteins in intracellular cholesterol transport and in maintaining cell cholesterol balance. Underexpression of NPC1 in concert with under-expression of ABCA1 would result in increased cholesterol accumulation and increased AD risk. We examined a functional polymorphism in the ABCA1 promoter region (-477, rs2422493), and four NPC1 polymorphisms in exon 6 (rs18050810), intron 20 (rs4800488), intron 22 (rs2236707), and intron 24 (rs2510344) capturing 85% of genetic variability in the Hap Map Caucasian (CEU) population, in a group of 631 Spanish AD patients and 731 controls. Subjects carrying both the ABCA1 (-477) TT genotype and the NPC1 (exon 6) GG genotype (OR=1.89; 95% CI 1.04-3.41), NPC1 (intron 20) AA genotype (OR=2.05; 95% CI 1.26-3.33), NPC1 (intron 22) AA genotype (OR=2.05; 95% or NPC1 (intron 24) GG genotype (OR=1.89; 95% higher risk of developing AD than subjects without these risk genotypes. Testing for epistatic interaction between genes in the pathway of cholesterol metabolism might be useful for predicting AD risk.

A megalin polymorphism associated with promoter activity and Alzheimer's disease risk†‡§

Elevated cerebral levels of amyloid beta‐protein (Aβ) occur in Alzheimers disease (AD), yet only a few patients show evidence of increased Aβ production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Aβ. Megalin, which plays an important role in mediating Aβ clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.