Study on the association between SOAT1 polymorphisms, Alzheimer's disease risk and the level of CSF biomarkers.

Background: In Alzheimer's disease (AD) the beta-amyloid precursor protein is excessively cleaved into Abeta(42), causing the abundant amyloid plaque loads in affected brain areas. Sterol O-acyltransferase 1 (SOAT1) has been found to regulate the production of beta-amyloid precursor protein.

Methods: We genotyped 4 SOAT1 single nucleotide polymorphism (SNP) sites (rs2247071, rs2862616, rs3753526 and rs1044925) in 410 Finnish AD cases and 455 controls and conducted a single allele and genotypic distribution comparison as well as estimating the haplotype frequencies between cases and controls and the level of biomarkers in genotype and haplotype carriers.

Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.

Beta-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's disease (AD)-associated Abeta protein. BACE levels are elevated in AD brain, and increasing evidence reveals BACE as a stress-related protease that is upregulated following cerebral ischemia. However, the molecular mechanism responsible is unknown.

The association study between DHCR24 polymorphisms and Alzheimer's disease.

DHCR24 gene in chromosome 1 encodes seladin 1, a cholesterol synthesizing enzyme. Seladin 1 protects neurons from Abeta(42) mediated toxicity and participates in regulation of Abeta(42) formation by organizing the placement of APP cleaving beta-secretase in cholesterol-rich detergent-resistant membrane domains (DRMs). In Alzheimer's disease (AD) the level of seladin 1 in affected neurons is reduced, DRMs are disorganized and Abeta(42) formation is increased.

Insulin-degrading enzyme is genetically associated with Alzheimer's disease in the Finnish population.

The gene for insulin-degrading enzyme (IDE), which is located at chromosome 10q24, has been previously proposed as a candidate gene for late-onset Alzheimer's disease (AD) based on its ability to degrade amyloid beta-protein. Genotyping of single nucleotide polymorphisms (SNPs) in the IDE gene in Finnish patients with AD and controls revealed SNPs rs4646953 and rs4646955 to be associated with AD, conferring an approximately two-fold increased risk. Single locus findings were corroborated by the results obtained from haplotype analyses.

Effects of Protostrongylus sp. and Pneumocystis sp. on the pulmonary tissue and the condition of mountain and brown hares from Finland.

Mountain hares (Lepus timidus) and brown hares (Lepus europaeus) shot by hunters in several game management districts in southern and central Finland during the hunting season from September to the end of February 1998-2001 were examined for Protostrongylus sp. and Pneumocystis sp. Of the mountain hares, 96.

Genetic study evaluating LDLR polymorphisms and Alzheimer's disease.

We genotyped SNPs rs11668477, rs12983082, rs11669576, rs2738444, rs5925 and rs1433099 in 405 Finnish AD cases and 463 controls and conducted a single allele and genotypic distribution comparison and estimated the haplotype frequencies between cases and controls and evaluated the level of biomarkers in haplotype carriers. We observed that T allele of rs2738444 was overrepresented in AD women with p=0.014 (Bonferroni corrected p=0.

Association analysis of peroxisome proliferator-activated receptor gamma polymorphisms and late onset Alzheimer's disease in the Finnish population.

Alzheimer's disease (AD), especially late-onset AD (LOAD), is a complex disease. To date, the only established genetic risk factor for LOAD is apolipoprotein E (APOE) epsilon4, which explains partially the risk of the disease and modifies the age of onset. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates the transcription of BACE1 as well as inflammatory responses in the brain and atherosclerotic risk factors known to be involved also in AD.

Ubiquilin 1 modulates amyloid precursor protein trafficking and Abeta secretion.

Ubiquilin 1 (UBQLN1) is a ubiquitin-like protein, which has been shown to play a central role in regulating the proteasomal degradation of various proteins, including the presenilins. We recently reported that DNA variants in UBQLN1 increase the risk for Alzheimer disease, by influencing expression of this gene in brain. Here we present the first assessment of the effects of UBQLN1 on the metabolism of the amyloid precursor protein (APP).

Artefactual effects of lipid-based cell transfection reagents on AbetaPP processing and Abeta production.

The study of amyloidogenic beta-amyloid precursor protein (AbetaPP) metabolism and amyloid beta protein (Abeta) production has been a major focus of Alzheimer's disease (AD) neuropathogenesis research. Cell transfection is a commonly employed method for assessing the effects of various genes on AbetaPP processing and Abeta production. Certain cell transfection reagents utilize lipid-based formulations that could potentially affect AbetaPP processing and Abeta production.

Interaction between presenilin 1 and ubiquilin 1 as detected by fluorescence lifetime imaging microscopy and a high-throughput fluorescent plate reader.

Presenilin 1 (PS1) in its active heterodimeric form is the catalytic center of the gamma-secretase complex, an enzymatic activity that cleaves amyloid precursor protein (APP) to produce amyloid beta (Abeta). Ubiquilin 1 is a recently described PS1 interacting protein, the overexpression of which increases PS1 holoprotein levels and leads to reduced levels of functionally active PS1 heterodimer. In addition, it has been suggested that splice variants of the UBQLN1 gene are associated with an increased risk of developing Alzheimer disease (AD).

Adiponectin gene haplotype is associated with preeclampsia.

We determined whether the polymorphism of the gene encoding adiponectin contributes to susceptibility to preeclampsia. The study involved 133 Finnish women with preeclampsia and 245 healthy control subjects. All women were genotyped for two single nucleotide polymorphisms (SNPs), SNP45 in exon 2 and SNP276 in intron 2, in the adiponectin gene.

Interleukin-6 promoter polymorphism and late-onset Alzheimer's disease in the Finnish population.

Recently, the involvement of the inflammatory response in Alzheimer's disease (AD) has received considerable attention. The gene encoding for interleukin-6 (IL-6) is interesting since IL-6 has been reported not only to be involved in immune functions but also in AD. We investigated whether the IL-6-174 G/C polymorphism is associated with late onset AD (LOAD) in the Finnish subjects.

Aromatase enzyme and Alzheimer's disease.

Aromatase enzyme encoded by CYP19 gene is responsible for the formation of estrone and estradiol from C19 androgens, androstenedione and testosterone. Several lines of evidence suggest an important role for the estrogens as well as androgens in the key pathogenic processes of Alzheimer's disease (AD) such as amyloid beta (Abeta) production, hyperphosporylation of tau protein, oxidative stress and apoptosis. Moreover, epidemiological studies suggest a neuroprotective role for estrogen in AD for which reason estrogen replacement therapies have been extensively studied as a way to improve the cognition and to lower the risk of AD.

Polymorphisms of interleukin-6, hepatic lipase and calpain-10 genes, and preeclampsia.

Objective: We determined whether single nucleotide polymorphisms (SNPs) in interleukin-6 (IL-6), hepatic lipase (HL) and calpain-10 (CAPN-10) genes contribute to susceptibility to develop preeclampsia.

Study Design: The study involved 133 preeclamptic and 115 healthy pregnant women who were genotyped for the C-174G polymorphism in the IL-6 gene, the G-250A polymorphism in the HL gene and SNP 43 (G/A) in the CAPN-10 gene. The chi2-test was used to assess genotype and allele frequency differences between the preeclamptic and control groups.

Effects of estradiol on spatial learning, hippocampal cytochrome P450 19, and estrogen alpha and beta mRNA levels in ovariectomized female mice.

The brain is an important target organ for peripherally synthesized estrogen but it also has its own steroid biosynthesis producing estrogen from testosterone catalyzed by the aromatase enzyme. This study examined the effects of estrogen treatment in two spatial memory tasks, one-arm-baited radial arm maze and a position discrimination task in the T-maze in ovariectomized female mice. Hippocampal cytochrome P450 19 (encoding aromatase), and estrogen receptor alpha and beta gene expressions were also measured using real time quantitative polymerase chain reaction analysis.

Plasma cell membrane glycoprotein-1 K121Q polymorphism in preeclampsia.

Background: Preeclampsia is a common hereditary disease with unclear aetiology and various genetic and environmental components. We wanted to determine whether genetic variability in the gene encoding plasma cell membrane glycoprotein-1 (PC-1) contributes to individual susceptibility to the development of preeclampsia.

Methods: The case-control study involved 133 women with preeclampsia and 115 healthy controls.

Locomotor activity and evoked dopamine release are reduced in mice overexpressing A30P-mutated human alpha-synuclein.

We have generated a transgenic mouse line overexpressing mutated human A30P alpha-synuclein under the control of the prion-related protein promoter. Immunohistology revealed mutated human A30P alpha-synuclein protein in numerous brain areas, but no gross morphological changes, Lewy bodies, or loss of dopaminergic cell bodies. The transgenic mice displayed decreased locomotion, impaired motor coordination, and balance.

APP substitutions V715F and L720P alter PS1 conformation and differentially affect Abeta and AICD generation.

The 37-43 amino acid Abeta peptide is the principal component of beta-amyloid deposits in Alzheimer's disease (AD) brain, and is derived by serial proteolysis of the amyloid precursor protein (APP) by beta- and gamma-secretase. gamma-Secretase also cleaves APP at Val50 in the Abeta numbering (epsilon cleavage), resulting in the release of a fragment called APP intracellular domain (AICD). The aim of this study was to determine whether amino acid substitutions in the APP transmembrane domain differentially affect Abeta and AICD generation.

Tissue inhibitor of metalloproteinase 1 adenoviral gene therapy alone is equally effective in reducing restenosis as combination gene therapy in a rabbit restenosis model.

Neointimal formation is a common feature after angioplasty, bypass grafting and stenting. Angioplasty damages endothelium, causing pathological changes in arteries which lead to smooth muscle cell proliferation, synthesis of extracellular matrix components and eventually restenosis formation. Adenoviruses offer an efficient transgene expression in the vascular system.

Estrogen receptor beta gene variants are associated with increased risk of Alzheimer's disease in women.

We investigated the association of five intronic single-nucleotide polymorphism (SNP) at the estrogen receptor beta (ESR2) gene locus and the susceptibility of developing Alzheimer's disease (AD) in 387 subjects with clinically diagnosed probable AD and 467 cognitively normal individuals derived from eastern Finland. According to our results, variation in the ESR2 gene is associated with an increased risk of AD in women, whereas it does not contribute to the disease susceptibility in men. More specifically, in women, the allele T and the genotype T/T of two of the studied ESR2 gene SNPs (SNP2 and SNP3) were more frequent in AD women than in cognitively normal control women (P=0.

Tumour necrosis factor-alpha gene haplotype is associated with pre-eclampsia.

We determined whether polymorphisms in the promoter region of the tumour necrosis factor alpha (TNF-alpha) gene contributes to differences in susceptibility to develop pre-eclampsia. The study involved 133 pre-eclamptic and 115 healthy pregnant women who were genotyped for the G-308A polymorphism of the TNF-alpha gene. The frequency of the G-308A allele was more common in the pre-eclampsia group than among the controls (P=0.

Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism.

Gene transfer to the vessel wall using vascular endothelial growth factors (VEGFs) has shown therapeutic potential for the treatment of restenosis. In this study, we evaluated the effect of catheter-mediated adenoviral (Ad) gene transfer of the mature form of VEGF-D (VEGF-D(DeltaNDeltaC)) in balloon-denuded cholesterol-fed rabbit aorta. AdLacZ was used as a control.

Family-based association between Alzheimer's disease and variants in UBQLN1.

Background: Recent analyses suggest that the known Alzheimer's disease genes account for less than half the genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22.

Methods: We evaluated 19 single-nucleotide polymorphisms in three genes within the chromosome 9q linkage region in 437 multiplex families with Alzheimer's disease from the National Institute of Mental Health (NIMH) sample (1439 subjects).

Genetic analysis of BDNF and TrkB gene polymorphisms in Alzheimer's disease.

According to previous biochemical and genetic findings, brain-derived neurotrophic factor (BDNF), via activation of its tyrosine kinase receptor B (TrkB), is considered as a plausible candidate for contributing to Alzheimer's disease (AD). To examine the genetic association of BDNF and TrkB genes with AD, we genotyped multiple single nucleotide polymorphisms (SNPs) within these genes among 375 Finnish AD patients and 460 control subjects. Single locus and multi-loci haplotype association analyses of BDNF and TrkB gene SNPs did not reveal significant differences between unstratified AD and control groups.