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Biomedical subjects

S Sorbi

Publications and source records attributed to S Sorbi.

At least 91 records · Page 5Linked to original sources
PubMed1996

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.

Age of Onset↗
PubMed1995

Apolipoprotein E in sporadic and familial Creutzfeldt-Jakob disease.

We assessed the apolipoprotein E (ApoE) genotype in 49 sporadic and ten familial Creutzfeldt-Jakob disease (CJD) patients, in seven healthy siblings with a PRNP mutation and in 84 controls. In sporadic CJD, ApoE genotypes and allelic frequencies do not significantly differ from that of controls. No influence of ApoE genotypes on age at onset was found. In familial cases, the disease appeared in mutated subjects showing the same ApoE genotype as members who have not yet developed CJD. Our results provide further evidence that ApoE is not a risk factor for CJD.

Aged↗
PubMed1995

Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.

Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.

Alzheimer Disease↗
PubMed1995

ApoE genotype and familial Alzheimer's disease: a possible influence on age of onset in APP717 Val-->Ile mutated families.

Recent studies have shown a genetic association of the apolipoprotein E (ApoE) epsilon 4 allele with late onset familial and sporadic Alzheimer's disease (AD). In this study we analysed the possible association of the genetic polymorphism of the ApoE gene with age of onset in Italian familial Alzheimer's disease (FAD) families including two early onset familial Alzheimer's (EOFAD) families with the APP717 Val-->Ile mutation in the amyloid precursor protein (APP) gene on chromosome 21. In none of the FAD families analysed was there a significant effect of the ApoE genotype on the age of onset with the exception of one of the two mutated EOFAD families in which the epsilon 2 allele delayed the age of onset.

Age Factors↗
PubMed1995

Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease.

We found a new familial Alzheimer's disease kindred in which the disease cosegregates with the APP717Val-->Ile mutation and in which all of the three most common apolipoprotein E (ApoE) alleles are represented. We studied the relationship between ApoE genotype and the clinical expression of the disease and found that in this amyloid precursor protein-mutated family, ApoE genotype influences the age at onset of the disease. Three mutated subjects heterozygous for the epsilon 4 allele had the earliest age at onset in this family, subjects heterozygous for the epsilon 2 allele had the latest age at onset, and subjects homozygous for the epsilon 3 allele had an intermediate age at onset. In this large kindred we also found an amyloid precursor protein-mutated subject 2.4 standard deviations older than the mean age at onset without clinical signs and symptoms of the disease and carrying the epsilon 2/epsilon 3 genotype.

Adult↗
PubMed1995

Alterations in metabolic properties in fibroblasts in Alzheimer disease.

Alzheimer disease (AD) leads to alterations in several biochemical properties in cultured skin fibroblasts. Because abnormal glucose metabolism has been reported in both in vivo and in vitro studies of the brain, we examined glucose and glutamine oxidation and lactate production in cultured skin fibroblasts from nine patients with familial AD, 19 with sporadic AD, and 20 age-matched controls. The production of CO2 from glucose and glutamine was significantly lower in both groups of Alzheimer fibroblasts compared to controls after 10 min or 1, 2, and 4 h of incubation. The reduction in CO2 production was most evident after 1 h of incubation with either (U-14C)-glucose or (U-14C)-glutamine. Lactate concentration was comparable in all groups at any time of incubation. These findings suggest that processes that require mitochondrial function as glucose or glutamine oxidation are altered in AD and provide evidence that complex metabolic differences are expressed in cultured nonneuronal cells from Alzheimer patients.

Aged↗
PubMed1994

ApoE allele frequencies in Italian sporadic and familial Alzheimer's disease.

Recent studies have provided evidence of association of apolipoprotein E (ApoE) epsilon 4 allele and late onset familial and sporadic Alzheimer's disease (AD). Epidemiological studies have established allelic variation at the ApoE locus. We have analyzed the ApoE gene polymorphism in a sample of 446 Italian subjects. Our data confirm a significant association between epsilon 4 allele and sporadic AD. The frequency of epsilon 4 allele in early onset familial AD patients was comparable to control values suggesting that epsilon 4 allele does not represent a risk factor for early onset familial AD (EOFAD). Moreover, we found a not previously reported association between ApoE epsilon 2 allele and sporadic AD and EOFAD.

Age of Onset↗
PubMed1994

Molecular genetics of Alzheimer's disease in Italian families.

We screened 11 families from different regions of Italy by direct sequencing of exon 17 of the APP gene. Two unrelated families carried the APP717 mutation segregating with the disease. These two families originate from two Italian regions which are considered genetically separate. Published studies have demonstrated the presence of the APP717 Val-->Ile mutation in kindreds of British or Japanese origin with early onset familial Alzheimer's disease. These data suggest that the APP717 mutation is not confined to islander families which may share common founders. From the molecular genetic point of view we also did linkage analysis. Several families, in fact, have not shown a linkage with chromosome 21 and the resolution of this dilemma required investigation of those pedigrees both with additional markers from chromosome 21 and with markers from other chromosomes.

Alzheimer Disease↗
PubMed1993

Cerebral soluble ubiquitin is increased in patients with Alzheimer's disease.

A study concerning the amount of soluble ubiquitin in different cortical and subcortical regions of brains from patients with Alzheimer's disease compared to the amount in normal brains is presented. Several samples from 9 brain regions were processed and analyzed by liquid chromatography. In almost all the investigated cerebral regions the soluble ubiquitin content was significantly higher in pathologic tissue than in normal tissue. The primary structure of ubiquitin isolated from brain tissue affected by Alzheimer's degenerative processes was determined and resulted to be identical to normal human ubiquitin. These findings, together with the detection of polyubiquitinated proteins in paired helical filaments of neurofibrillary tangles described by several authors, suggest that an impairment of the process of intracellular, ubiquitin-dependent proteolysis might play an important role in the pathogenesis of this neurodegenerative disease. On the other hand, the expression of the correct polypeptide sequence in brain with Alzheimer's disease seems to exclude a mutation of the polyubiquitin gene as a cause of these alterations.

Adult↗
PubMed1993

Effect of phosphatidylserine on free radical susceptibility in human diploid fibroblasts.

We studied the effect of phosphatidylserine (PdtSER) on oxygen metabolite toxicity in skin fibroblast cell lines from apparently normal subjects. Fibroblast damage was produced by the generation of oxygen metabolites during the enzymatic oxidation of acetaldehyde by xanthine-oxidase (Xo). In order to quantify cell damage, we measured lactate dehydrogenase (LDH) activity in culture medium and cell viability in fibroblast cultures, with and without preincubation for 4 days with PdtSER 13 microM, after Xo incubation. We found a significant increase of LDH activity in culture medium of cells without preincubation with PdtSER. No significant increase of LDH activity was observed in the same cell lines after preincubation with PdtSER.

Acetaldehyde↗
PubMed1993

Molecular genetics of Alzheimer's disease.

At present it is not clear whether Alzheimer's disease is a single disease, a complex syndrome, or a heterogeneous ill-defined group of disorders. In the last few years significant progress has been made in identifying and describing its different manifestations, as well as the underlying biological mechanisms. Modern molecular biology techniques have provided new insights into possible etiological mechanisms. Linkage analysis and gene sequencing studies have produced evidence of a possible locus on chromosome 21 in a small group of families with early onset familial Alzheimer's disease (FAD). It was shown that another small group of early onset FAD families develops the disease as a result of mutations in the gene coding for the beta-amyloid precursor protein, and that in a larger subgroup of early onset families the disease appears to be caused by an unidentified gene on chromosome 14. Several other early onset FAD families are clearly not linked to any of these loci, suggesting that other abnormal genes, probably on different chromosomes, might be the cause of the disease in these families. Finally, it was recently shown that the epsilon 4 allele of apolipoprotein E (ApoE) gene, which has been mapped to chromosome 19, is associated with an increased risk of developing the disease in late onset FAD families and sporadic cases. These results not only evidence that Alzheimer's disease is a genetically heterogeneous disorder, but also delineate new approaches in the study of the etiological and pathogenetic mechanisms of Alzheimer's disease.

Alzheimer Disease↗
PubMed1993

Stimulation of glycolytic key enzymes in cerebral cortex by insulin.

In adult male Wistar rats, a test was conducted to find whether or not insulin, administered intracerebroventricularly, would stimulate the activities of the glycolytic key enzymes hexokinase and phosphofructokinase in brain tissue as in non-neuronal tissue. The data clearly demonstrated an increase in these enzyme activities in cerebral cortex by approximately 20% after 80 mU insulin, whereas the increase in the hippocampus was just short of statistical significance. It is concluded that insulin controls glycolytic flux in the brain, and the suggestion that any perturbation in insulin signal transduction has severe impacts on brain glucose metabolism seems justified.

Animals↗
PubMed1993

Analysis of the c-FOS gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alzheimer's disease.

The c-FOS gene product, a putative transacting transcriptional regulator of the amyloid precursor protein (APP) gene, is a candidate locus for the familial Alzheimer's disease (FAD) mutation on chromosome 14 (FAD14). In light of this functional relationship, we investigated the nucleotide sequence and segregation of c-FOS and the nucleotide sequence of the 5' APP promoter. Single-stranded conformational polymorphisms (SSCPs) in the c-FOS gene revealed that c-FOS closely cosegregates with the FAD14 gene but does not show allelic association with FAD. A conservative third-position T-->C mutation was demonstrated in exon 2 (codon 84) of c-FOS, and a C-->G substitution was detected at -209 bp in the 5' promoter of APP. Neither were unique to FAD and are unlikely to be pathogenic or secondary modifiers of the FAD phenotype. We conclude that the c-FOS open reading frame is probably not the site of the FAD14 locus, but we cannot exclude the existence of modifier loci on chromosome 21.

Adult↗
PubMed1992

Free radical injury in skin cultured fibroblasts from Alzheimer's disease patients.

Oxygen radical production is postulated to be a major cause of cell damage in aging. We have studied the response to toxic oxygen metabolites of fibroblast cell lines derived from skin biopsies of patients with familial and sporadic Alzheimer's disease compared with those derived from normal controls. Fibroblasts were damaged by the generation of oxygen metabolites during the enzymatic oxidation of acetaldehyde by 50 mU of xanthine-oxidase. To quantify cell damage we measured lactate dehydrogenase activity in the culture medium and cell viability in fibroblast cultures from four normal subjects, five FAD, and four AD patients after 2 hours of Xo incubation. We found a significant increase of LDH activity in FAD vs. controls and also in AD vs. controls, suggesting that AD cells are more susceptible to oxygen radical damage than are normal controls.

Alzheimer Disease↗
PubMed1992

Alzheimer skin fibroblasts show increased susceptibility to free radicals.

We have studied the response to toxic oxygen metabolites of fibroblasts derived from skin biopsies of 5 patients with familial (FAD) and 4 with sporadic (AD) Alzheimer's disease compared with those derived from 4 normal controls. Fibroblasts were damaged by the generation of oxygen metabolites during the enzymatic oxidation of acetaldehyde by 50 munits of xanthine-oxidase (Xo). To quantify cell damage we measured lactate dehydrogenase (LDH) activity in the culture medium and cell viability in fibroblast cultures. We found a significant increase in LDH activity in the FAD vs. controls and also in the AD vs. controls.

Acetaldehyde↗