Absence of a connection between Alzheimer's disease and complement markers

The hypothesis of a linkage between Alzheimer's disease (AD) (presenile dementia) and the complement components C2, C4, Bf linked to the Major Histocompatibility Complex has been investigated in a large family originating from Calabria, in which AD is transmitted as an autosomal dominant monogenic mendelian trait. The analysis of complotypes of 33 members of a pedigree, from which 10 individuals are affected, allowed to demonstrate that there wasn't any linkage between AD and those markers. Furthermore, no complete or partial deficiency in the C2, C4, Bf components has been observed in affected patients.     

Absence of linkage between transcobalamin II and ABO

Summary In a linkage analysis of 29 pedigrees with a total of 196 individuals, absence of close linkage between transcobalamin II (TC2) and ABO is demonstrated. Recombination fraction values of 相似文献   

Genetic linkage between hereditary hemochromatosis and HLA.

A large Mormon pedigree of a proband with hemochromatosis was studied, using transferrin saturation as the quantitative phenotypic trait. The analysis indicated that the inheritance of hemochromatosis was recessive, with partial expression in some heterozygotes. The lod score of 6.88 (theta = .0) was strongly indicative of linkage between the hemochromatosis locus and the human major histocompatibility (HLA) loci.     

Genetic hemochromatosis and HLA linkage

Summary We previously reported five families with primary, genetic (idiopathic) hemochromatosis in whom HLA typing of subjects indicated that a homozygous-heterozygous mating had almost certainly occurred and in whom inheritance of the disease trait was best explained by an autosomal recessive mode of inheritance. However, in one family, two children apparently homozygous for hemochromatosis did not manifest overt evidence of the disease, and alternative explanations were postulated, including autosomal dominant inheritance in this family. Subsequent study of the family members, including repeat HLA-DR serology with more recently defined antisera and DNA genotyping at the HLA-DR locus has, we believe, provided the true explanation for the previous apparent anomaly and adds further evidence for the tight linkage of the disease to the HLA-A locus.     

Alzheimer's disease meets the ubiquitin-proteasome system

Ubiquitin-positive deposits are histopathologically found in patients with Alzheimer's disease (AD). It is not understood why ubiquitin is accumulated in intra- and extra-cellular deposits or how it is involved in AD pathogenesis. Interestingly, recent evidence, including studies of E2-25K/Hip-2, has elucidated the molecular mechanism of the ubiquitin-proteasome system (UPS) malfunction in AD. The neurotoxicity and proteasome inhibition by Abeta, a main cause of AD pathogenesis, are mediated by increased E2-25K/Hip-2 in the brains of patients with AD. Furthermore, E2-25K/Hip-2 is required for the neurotoxicity that is mediated by a ubiquitin B mutant (UBB+1), which is a potent inhibitor of proteasomes that is found in patients with AD. Intensive research is required to identify the components of the UPS that are involved in AD pathogenesis.     

Absence of detectable linkage between the G and H blood group loci in the pig

Morton's lod score method used for the analysis of data from 168 backcross matings (1094 offspring) did not indicate linkage between the G and H blood group loci of the pig. Linkage closer than 0.413 could be excluded at the 1% significance level.     

Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer's disease

Alzheimer's disease is the most common progressive neurodegenerative disorder characterized by the abnormal deposition of amyloid plaques, likely as a consequence of an incorrect processing of the amyloid-β precursor protein (AβPP). Dysfunctions in both the ubiquitin-proteasome system and autophagy have also been observed. Recently, an extensive cross-talk between these two degradation pathways has emerged, but the exact implicated processes are yet to be clarified. In this work, we gained insight into such interplay by analyzing human SH-SY5Y neuroblastoma cells stably transfected either with wild-type AβPP gene or 717 valine-to-glycine AβPP-mutated gene. The over-expression of the AβPP mutant isoform correlates with an increase in oxidative stress and a remodeled pattern of protein degradation, with both marked inhibition of proteasome activities and impairment in the autophagic flux. To compensate for this altered scenario, cells try to promote the autophagy activation in a HDAC6-dependent manner. The treatment with amyloid-β(42) oligomers further compromises proteasome activity and also contributes to the inhibition of cathepsin-mediated proteolysis, finally favoring the neuronal degeneration and suggesting the existence of an Aβ(42) threshold level beyond which proteasome-dependent proteolysis becomes definitely dysfunctional.     

The HLA system and the analysis of multifactorial genetic disease

The human leukocyte antigen (HLA) system comprises closely linked genes controlling highly polymorphic proteins involved in the presentation of peptides to the T-cell receptor. Specific alleles at HLA loci are associated with diseases, often those suspected to be of autoimmune aetiology. Many of these associations result from linkage disequilibrium between the HLA gene studied and other HLA genes or non-HLA gebes close by. Owing to its high level of polymorphism and its candidate role in many diseases, HLA was the first system used in many techniques of genetic mapping, such as affected-sib-pair analysis and association (linkage disequilibrium) studies. Much remains unknown about the reasons why diseases are associated with HLA. Experience gained from HLA has, however, shown how other loci involved in complex traits can be identified by studying families with multiple affected cases or sib pairs, followed by linkage-disequilibrium mapping and then analysis of candidate genes.     

Genetic considerations on association between HLA and disease

Summary Blood specimens from a random sample of 981 South African Negroid females were typed electrophoretically inter alia for their G-6-PD phenotypes. The allele frequency for Gd^B and Gd^nonB was found to be 0.8126 and 0.1874 respectively. Calculating the number of individuals expected for each phenotypic class, a highly significant deviation from the Hardy-Weinberg equilibrium became manifest, i.e. there was a deficit of 24.6% of heterozygotes and an excess of 12.3% of each of the two classes of homozygotes.Several possible reasons for this discrepancy e.g. the effects of pooling sub-samples, selection and misclassifications due to insufficient staining were examined and were found not to be likely explanations for the observed phenomenon. Instead, the result is interpreted as due to only 3–4 stem cells which give rise to the haematopoetic system in man.Part of this work was presented at the biennial Congress of the Deutsche Gesellschaft für Anthropologie und Humangenetik held in Vienna, September 22–25, 1975Supported by a research fellowship (1975/76) granted by the Alexander von Humboldt-Stiftung, Bonn-Bad GodesbergSupported by the Deutsche Forschungsgemeinschaft (DFG), Bonn-Bad Godesberg     

纤溶酶系统与阿尔茨海默症

阿尔茨海默症(Alzheimer's disease,AD)是一种中枢神经系统进行性的退变疾病,其病因目前尚未确定。越来越多的遗传学和生物化学证据显示β淀粉样蛋白(amyloid β,Aβ)是AD发病的主要病理因子。本文介绍了大脑纤溶酶系统与Aβ相互作用的分子机理,通过上调大脑中纤溶酶的表达,可以清除Aβ,这可能为防治AD提供了新的治疗靶点。最新研究结果表明PAI-1的小分子抑制剂和他汀类药物可以通过纤溶酶系统来调控Aβ的降解,这类药物有望成为治疗和预防AD的新药。     

Absence of genetic linkage between A1BG, PGD and HPX loci in rabbits

Linkage relationships between A1BG, PGD, and HPX loci of rabbits were studied on segregation data in backcross matings. No sign of linkage between the three studied loci was found.     

Relation between nicotine intake and Alzheimer's disease.

OBJECTIVE--To study the association between Alzheimer''s disease and nicotine intake through smoking. DESIGN--Population based case-control study. SETTING--City of Rotterdam and four northern provinces of The Netherlands. SUBJECTS--198 patients with early onset Alzheimer''s disease, 198 controls matched for age and sex, and families of 17 patients in whom Alzheimer''s disease was apparently inherited as an autosomal dominant disorder. MAIN OUTCOME MEASURES--Age of onset of dementia, relative risk of Alzheimer''s disease. RESULTS--89 of 193 patients with Alzheimer''s disease had a history of smoking compared with 102 of 195 controls. Among the patients and controls with a family history of dementia, smoking was significantly less common in those with dementia (40/95 with dementia v 55/96 controls; relative risk 0.35; 95% confidence interval 0.16 to 0.78). The risk of Alzheimer''s disease decreased with increasing daily number of cigarettes smoked before onset of disease (relative risk 0.3 in those smoking greater than 21/day v 1 in non-smokers). In six families in which the disease was apparently inherited as an autosomal dominant disorder, the mean age of onset was 4.17 years later in smoking patients than in non-smoking patients from the same family (p = 0.03). CONCLUSIONS--These findings suggest an inverse association between smoking and Alzheimer''s disease, although smoking cannot be advocated for other health reasons. We speculate that nicotine may have a role in the aetiology of both Alzheimer''s disease and Parkinson''s disease.     

Interactions between the amyloid and cholinergic mechanisms in Alzheimer's disease

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by memory and cognitive loss, the formation of senile plaques containing amyloid-beta (Abeta) peptide, degeneration of the cholinergic neurons and the development of neurofibrillary tangles. The build-up of Abeta is considered to be a central feature in the pathogenesis of AD. However, other critical molecular and neurochemical alterations too occur, such as a cholinergic dysfunction. As concerns the pathomechanism of the disease, both the amyloid cascade hypothesis and the cholinergic hypothesis of AD are widely accepted. This review surveys recent in vitro and in vivo experimental evidence relating to these two hypotheses. Bidirectional pathways linking them as regards the cholinergic neurotoxicity of Abeta and the regulatory mechanisms of cholinergic receptor activation or enzyme inhibition in the processing of the amyloid precursor protein are also discussed. Further work is warranted to elucidate the exact effects in the interactions between the cholinergic and amyloid hypotheses of the candidate drugs used in AD therapy.     

Absence of linkage between the serum cholinesterase (CHE1) and rhesus (RH) loci

Summary Twenty-two informative families were analyzed for the CHE1: RH linkage relationship. The total results exclude loose linkage until =0.28.     

Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.