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Biomedical subjects

L Lannfelt

Publications and source records attributed to L Lannfelt.

At least 37 records · Page 2Linked to original sources
PubMed2000

Quantification of Alzheimer amyloid beta peptides ending at residues 40 and 42 by novel ELISA systems.

BACKGROUND: The amyloid beta (Abeta) peptide is a key molecule in the pathogenesis of Alzheimer's disease. Reliable methods to detect and quantify soluble forms of this peptide in human biological fluids and in model systems, such as cell cultures and transgenic animals, are of great importance for further understanding the disease mechanisms. In this study, the application of new and highly specific ELISA systems for quantification of Abeta40 and Abeta42 (Abeta peptides ending at residues 40 or 42, respectively) in human cerebrospinal fluid (CSF) are presented. MATERIALS AND METHODS: Monoclonal antibodies WO-2, G2-10 and G2-11 were thoroughly characterized by (SPOT) epitope mapping and immunoprecipitation/mass spectrometry. We determined whether aggregation affected the binding capacities of the antibodies to synthetic peptides and whether components of the CSF affected the ability of the antibodies to bind synthetic Abeta1-40 and Abeta1-42 peptides. The stability of Abeta40 and Abeta42 in CSF during different temperature conditions was also studied to optimize sample handling from lumbar puncture to Abeta assay. RESULTS: The detection range for the ELISAs were 20-250 pM. The intra-assay variations were 2% and 3%, and the inter-assay variations were 2% and 10% for Abeta40 and Abeta42, respectively. The antibodies specifically detected the expected peptides with equal affinity for soluble and fibrillar forms of the peptide. The presence of CSF obstructed the recognition of synthetic peptides by the antibodies and the immunoreactivity of endogenous CSF Abeta decreased with increasing storage time and temperature. CONCLUSIONS: This study describes highly sensitive ELISAs with thoroughly characterized antibodies for quantification of Abeta40 and Abeta42, an important tool for the understanding of the pathogenesis of Alzheimer's disease. Our results pinpoint some of the difficulties associated with Abeta quantification and emphasize the importance of using a well-documented assay.

Albumins↗
PubMed1999

Tau gene polymorphisms and apolipoprotein E epsilon4 may interact to increase risk for Alzheimer's disease.

In an effort to analyze the genetic role of tau in Alzheimer's disease (AD), 17 polymorphisms were identified. Eleven of these polymorphisms were in complete linkage disequilibrium and segregated as two haplotypes, A and B. The A and B haplotypes were investigated in 269 AD cases and 238 controls from two different sources, a clinic-based group (mean age of onset 65+/-9 years), and a population-based group (mean age of onset 80+/-5 years). A synergistic effect between the common tau genotype AA and apolipoprotein E (APOE epsilon4) was found in the clinic-based AD group. Our study suggests that the common tau genotype AA may interact with APOE epsilon4 in increasing the risk of AD in a subgroup of the AD population.

Aged↗
PubMed1999

Inhibition of prolylendopeptidase does not affect gamma-secretase processing of amyloid precursor protein in a human neuroblastoma cell line.

Abeta peptides are major components of the amyloid plaques that characterize Alzheimer's disease. The enzyme activities (beta- and gamma-secretases) involved in generating Abeta from amyloid precursor protein (APP) are unidentified. It has been suggested that prolylendopeptidase (PEP), an oligopeptidase that normally cleaves after proline residues, could also cleave after the alanine at position 42 of Abeta to generate Abeta42. We investigated whether inhibition of PEP activity in human neuroblastoma cells affected Abeta levels in cell culture media. An SH-SY5Y cell line expressing SPA4CT, encoding the C-terminal 100 residues of APP and the signal sequence, was used. Only gamma-secretase activity is required for Abeta production in this cell line. The PEP inhibitor Fmoc-AlaPro-CN (10 microM) reduced PEP activity in these cells by approximately 95% in the absence of significant toxicity, but had no effect on Abeta40 or Abeta42 levels in cell culture media. We conclude that PEP is unlikely to be involved in gamma-secretase processing of APP.

Amino Acids↗
PubMed1999

Construction of a detailed physical and transcript map of the FTDP-17 candidate region on chromosome 17q21.

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant condition clinically characterized by behavioral, cognitive, and motor disturbances. Until now, at least 13 different FTDP-17 families that show linkage to chromosome 17q21 have been described. To characterize the FTDP-17 candidate region, flanked by the markers D17S1789 and D17S1804, we constructed a physical map in P1 and PAC clones. A detailed transcript map was generated by positioning known genes and EST clusters to the physical map. In total, we investigated 150 STSs mapped to this region. In addition, novel transcripts were isolated by exon-trapping. We were able to localize 19 known genes and a number of ESTs to this chromosomal region. Furthermore, seven novel genes were identified for which we isolated the full-length sequence.

Base Sequence↗
PubMed1999

A DLST genotype associated with reduced risk for Alzheimer's disease.

Recent studies suggest that variants of the DLST gene alter the risk of AD. DLST encodes the core subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex, which is deficient in AD. The authors report that in 247 US white subjects, homozygosity for DLST A19,117, T19,183 was associated with a reduced risk of AD (odds ratio [OR] = 0.35, p = 0.018). The reduced risk was marked in subjects who did not carry the apolipoprotein (APOE)-4 allele (OR = 0.16, p = 0.014). Further study of DLST in AD appears warranted.

Acyltransferases↗
PubMed1999

Protein kinase C and amyloid precursor protein processing in skin fibroblasts from sporadic and familial Alzheimer's disease cases.

Non-amyloidogenic alpha-secretase processing of amyloid precursor protein (APP) is stimulated by protein kinase C (PKC). Levels and activity of PKC are decreased in sporadic Alzheimer's disease skin fibroblasts. We investigated whether alterations in PKC and PKC-mediated APP processing occur also in fibroblasts established from individuals with familial Alzheimer's disease APP KM670/671NL, PS1 M146V and H163Y mutations. These pathogenic mutations are known to alter APP metabolism to increase Abeta. PKC activities, but not levels, were decreased by 50% in soluble fractions from sporadic Alzheimer's disease cases. In contrast, familial Alzheimer's disease fibroblasts showed no significant changes in PKC enzyme activity. Fibroblasts bearing the APP KM670/671NL mutation showed no significant differences in either PKC levels or PKC-mediated soluble APP (APPs) secretion, compared to controls. Fibroblasts bearing PS1 M146V and H163Y mutations showed a 30% increase in soluble PKC levels and a 40% decrease in PKC-mediated APPs secretion. These results indicate that PKC deficits are unlikely to contribute to increased Abeta seen with APP and PS1 mutations, and also that PS1 mutations decrease alpha-secretase derived APPs production independently of altered PKC activity.

Adult↗
PubMed1999

Cerebrospinal fluid A beta42 is increased early in sporadic Alzheimer's disease and declines with disease progression.

All mutations known to cause familial Alzheimer's disease (AD) act by increasing the levels of soluble beta-amyloid peptide (A beta), especially the longer form, A beta42. However, in vivo elevation of soluble A beta in sporadic AD has so far not been shown. In the present study, we used enzyme-linked immunosorbent assays specific for A beta42 and A beta40 to investigate cerebrospinal fluid from sporadic AD at different stages of disease severity, to clarify the roles of A beta42 and A beta40 during disease progression. We also evaluated three other groups--one group of patients with mild cognitive impairment who were at risk of developing dementia, a cognitively intact, nondemented reference group diagnosed with depression, and a perfectly healthy control group. We found that A beta42 is strongly elevated in early and mid stages of AD, and thereafter it declines with disease progression. On the contrary, A beta40 levels were decreased in early and mid stages of AD. The group of cognitively impaired patients and the depression reference group had significantly higher levels of A beta42 than the healthy control group, implying that A beta42 is increased not only in AD, but in other central nervous system conditions as well. Our data also point out the importance of having thoroughly examined control material. The initial increase and subsequent decrease of A beta42 adds a new biochemical tool to follow the progression of AD and might be important in the monitoring of therapeutics.

Aged↗
PubMed1999

Expression of presenilin 1 mRNA in rat peripheral organs and brain.

At least 50 different mutations in the presenilin 1 gene have been shown to cause early onset familial Alzheimer's disease. Although presenilin 1 has an obvious role in the pathogenesis of Alzheimer's disease, its function is still unknown. In the present study, the occurrence and distribution of presenilin 1 mRNA was examined in rat peripheral organs as well as in the brain by in situ hybridization histochemistry, using a radiolabelled oligonucleotide probe. In comparison to the brain, a high presenilin 1 mRNA expression was found in the testis, kidney, spleen, adrenal gland and thymus. It was also observed in skeletal muscle, liver, small intestine and lung, whereas no presenilin 1 could be detected in the heart, spinal cord and pancreas. Since presenilin 1 mRNA was found to be abundant in peripheral tissues which apparently are not affected in Alzheimer's disease, additional functions of presenilin 1 are suggested, unrelated to its role in the pathological processes of the disease.

Adrenal Glands↗
PubMed1999

Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex.

The presenilin proteins are components of high-molecular-weight protein complexes in the endoplasmic reticulum and Golgi apparatus that also contain beta-catenin. We report here that presenilin mutations associated with familial Alzheimer disease (but not the non-pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of beta-catenin after activation of the Wnt/beta-catenin signal transduction pathway. As with their effect on betaAPP processing, the effect of PS1 mutations on trafficking of beta-catenin arises from a dominant 'gain of aberrant function' activity. These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin-beta-catenin protein complexes is central to this process.

Alzheimer Disease↗
PubMed1999

An angiotensin-converting enzyme gene polymorphism suggests a genetic distinction between ischaemic stroke and carotid stenosis.

BACKGROUND: Ischaemic cerebrovascular disease (ICVD) is a heterogeneous syndrome to which different genetic factors may contribute. We have investigated the distribution of alleles of the angiotensin-converting enzyme (ACE) gene, which has been suggested to be of possible importance in ischaemic stroke or cardiovascular disease, in groups of patients with ischaemic stroke and carotid artery stenosis (CS). MATERIALS AND METHODS: One hundred and thirty patients with ischaemic stroke and 68 patients with more than 50% stenosis of the internal carotid artery were investigated and compared with age- and sex-matched healthy control subjects. Alleles of an insertion/deletion polymorphism of the ACE gene were determined by one-stage polymerase chain reaction and visualized on agarose gels. RESULTS: There was a significant difference (P < 0.05) in the distribution of ACE alleles, homozygosity for the presumed susceptibility deletion allele being more common in patients with CS than in healthy control subjects. There was also a significant difference (P < 0.05) in patients with CS in comparison with matched ICVD patients without CS, both in allelic frequencies and in homozygosity for the deletion allele. CONCLUSIONS: Our results indicate that the ACE gene polymorphism may be a risk factor for the development of CS. The observed difference in ACE allele distribution may be seen as evidence for a genetic distinction between ICVD and CS, two clinically related conditions, which further supports the hypothesis that genetic factors are of importance for this group of diseases.

Aged↗
PubMed1999

Neuronal nicotinic receptor deficits in Alzheimer patients with the Swedish amyloid precursor protein 670/671 mutation.

The influence of beta-amyloid on cholinergic neurotransmission was studied by measuring alterations in nicotinic acetylcholine receptors (nAChRs) in autopsy brain tissue from subjects carrying the Swedish amyloid precursor protein (APP) 670/671 mutation. Significant reductions in numbers of nAChRs were observed in various cortical regions of the Swedish 670/671 APP mutation family subjects (-73 to -87%) as well as in sporadic Alzheimer's disease (AD) cases (-37 to -57%) using the nicotinic agonists [3H]epibatidine and [3H]nicotine, which bind with high affinity to both alpha3 and alpha4 and to alpha4 nAChR subtypes, respectively. Saturation binding studies with [3H]epibatidine revealed two binding sites in the parietal cortex of AD subjects and controls. A significant decrease in Bmax (-82%) for the high-affinity site was observed in APP 670/671 subjects with no change in K(D) compared with controls (0.018 nM APP 670/671; 0.036 nM control). The highest load of neuronal plaques (NPs) was observed in the parietal cortex of APP 670/671 brains, whereas the number of [3H]nicotine binding sites was less impaired compared with other cortical brain regions. Except for a positive significant correlation between the number of [3H]nicotine binding sites and number of NPs in the parietal cortex, no strict correlation was observed between nAChR deficits and the presence of NPs and neurofibrillary tangles, suggesting that these different processes may be closely related but not strictly dependent on each other.

Aged↗
PubMed1999

A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon 12 of the presenilin 1 gene: clinical and molecular characterization.

The presenilin 1 (PS-1) gene, recently identified on chromosome 14q24.3, is a major gene involved into the autosomal dominant forms of early onset Alzheimer's disease (EOAD). Mutations of the PS-1 gene are responsible for the majority of familial EOAD. We found a novel mutation in a Polish family with EOAD from the Poznań region. The mutation at codon 424 in exon 12 of the PS-1 gene leads to an amino acid substitution Leu-Arg in a transmembrane domain VIII of the presenilin 1 molecule. The change is predicted to have a drastic effect on the protein function because it is associated with a very early age of onset (a range of 30-35 years) and a quick progression (about a 4-5 years duration) of the disease.

Adult↗
PubMed1999

Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population.

The mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) is deficient in Alzheimer's disease (AD). The DLST gene encodes the core, dihydrolipoyl succinyltransferase (DLST) component of KGDHC, and recent reports indicate an association between polymorphisms of DLST and AD in both white and Japanese patients. We therefore examined the relationship between AD and the DLST and apolipoprotein E (APOE) genes in elderly (89 +/- 7 years) AD patients, in whom the epsilon4 allele of APOE (APOE4) is a weak risk factor for AD. Polymorphisms of DLST (A19,117G and T19,183C), shown to be of interest in previous studies, were analyzed by restriction fragment length polymorphism analysis after polymerase chain reaction amplification. In a series of 429 white subjects from two Jewish nursing homes, an association of APOE4 with AD was found only in patients homozygous for the G,C allele of DLST. Similar relationships occurred in the "very elderly" (> or =85 years, n = 302) subgroup of this series, and also in an autopsy series (n = 225) that included white subjects from the Jewish nursing homes as well as other white subjects. These findings suggest a relationship between APOE4 and a DLST locus in the pathogenesis of AD in very elderly subjects.

Acyltransferases↗
PubMed1998

Psychotic symptoms and apolipoprotein E genotypes in an elderly population.

BACKGROUND: Psychotic symptoms have been found to be more common in demented elderly persons. Genetic variation in the apolipoprotein E (APOE) gene is reported to be associated with variation in the risk of Alzheimer's dementia. This study reports on variables associated with psychotic symptoms including APOE, in demented and nondemented elderly persons. METHODS: A population of 668 elderly persons was examined. APOE genotype was available in 309 individuals. RESULTS: Psychotic symptoms were found to be associated with dementia, a previous psychiatric history, female gender, being less educated, disability in daily living and institutionalisation. In the nondemented group, psychotic symptoms were equally common in subjects with or without the epsilon 4 present. In the demented subjects, psychotic symptoms were slightly more common, although not significant, in subjects without the epsilon 4 genotype. CONCLUSIONS: There was no statistical significant difference in APOE genotype between subjects with and without psychotic symptoms, stratified by dementic diagnosis.

Activities of Daily Living↗
PubMed1998

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Alternative Splicing↗
PubMed1998

EEG slowing and cerebrospinal fluid tau levels in patients with cognitive decline.

We explored the relationship between cerebrospinal fluid (CSF) tau levels as indirect markers of tau-related pathology in Alzheimer's disease (AD) and EEG slowing, a typical neurophysiological finding in the disease. A positive correlation between CSF tau levels and ratio of alpha/delta global field power was found in 14 AD patients (r = 0.65, p = 0.01). This relationship was better approximated by polynomial fit of 2nd degree (p = 0.002). A subgroup of AD patients (n = 7) with higher tau levels and shorter duration of illness showed a strong relationship between CSF tau levels and alpha/theta (r = 0.83, p = 0.02), and alpha/delta (r = 0.87, p = 0.01) ratios of the global field power. There were no significant correlations between EEG slowing and CSF tau levels in 12 patients with mild cognitive dysfunction or in 14 healthy control subjects. That a strong inverse linear correlation exists in AD patients with higher levels of tau and shorter duration of illness may imply that with longer illness duration CSF tau levels decrease due to neuronal death.

Aged↗
PubMed1998

Wide range of disease onset in a family with Alzheimer disease and a His163Tyr mutation in the presenilin-1 gene.

OBJECTIVES: To describe clinical and genealogical data of a Swedish family with a His163Tyr mutation in the presenilin-1 gene (PS1) and to study the Alzheimer disease (AD) penetrance in this family. DESIGN: Interviews with relatives, studies of medical records, analysis of pedigree, physician examination of the affected individuals, and comparison with other families affected by AD with PS1 mutations. SETTING: Large university-affiliated hospital. PATIENTS AND OTHER PARTICIPANTS: Individuals with a His163Tyr mutation in PS1 and their relatives. RESULTS: A study of this family with a history of very early AD onset (mean age, 47 years) has been previously published, but an investigation of the extended family revealed a new pattern of onset, with a mean age at onset of 54 years (range, 44-65 years). In general, families with AD show a tight cluster of age at onset with high penetrance of the disease. However, in this family, an individual whose child carries the PS1 mutation died at age 67 years free from cognitive symptoms, indicating a very late age at onset or nonpenetration of the disease. No association between age at onset and disease duration was found. Furthermore, the disease duration did not differ between those having an early onset compared with those having a late onset. The earliest clinical manifestations were deficits in memory function and disorientation in time and place. Myoclonic jerks and epileptic seizures were common symptoms later in the disease. CONCLUSION: The large range in age at onset in this family with a uniform genetic basis for the disease, a His163Tyr mutation in PS1, supports the existence of other unknown genetic or environmental factors of importance for the expression of the AD phenotype.

Age of Onset↗