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Biomedical subjects

M Mullan

Publications and source records attributed to M Mullan.

At least 55 records · Page 3Linked to original sources
PubMed1998

Isoform-specific vasoconstriction induced by apolipoprotein E and modulation of this effect by Alzheimer's beta-amyloid peptide.

Abeta peptides are thought to be centrally involved in Alzheimer's disease (AD) pathogenesis, although Abeta's pathophysiological mechanisms remain to be elucidated. We previously showed that soluble beta-amyloid1-40 (Abeta) and Abeta1-42 exhibit vasoactive properties, and are able to promote vasoconstriction in rat aortae induced by an endogenous vasoconstrictor, endothelin-1. It is well established that the APOE epsilon4 allele confers risk for both familial and sporadic AD, as well as for hypertension. We now report that physiologic amounts (10 nM) of specific human recombinant apoE isoforms are vasoactive (E4 > E3, and not E2) in isolated rat aortae. In order to investigate if various apoE isoforms could modulate Abeta vasoactivity, we co-incubated Abeta1-40 with various isoforms of apoE in our tissue bath system. Our results show that, while none of the APOE isoforms are able to affect the maximum constriction induced by Abeta; the apoE E4 isoform synergistically enhances the rate of vasoconstriction induced by Abeta. Our data suggest that apoE may promote hypertension and contribute to AD pathogenesis via enhancement of vasoconstriction, and support a link between hypertension, cerebral amyloid angiopathy and AD.

Amyloid beta-Peptides↗
PubMed1998

Alzheimer's beta-amyloid vasoactivity: identification of a novel beta-amyloid conformational intermediate.

The beta-amyloid (A beta) peptide has previously been shown to enhance phenylephrine or endothelin-1 induced constriction of aortic rings in vitro. The characteristics of A beta vasoactivity (dose, fragment length, timing) suggest that the mechanism is distinct from A beta cytotoxicity. To identify which properties of A beta determine its biological activity on vessels, we investigated a number of A beta analogues and fragments, individually and in combination, including those that are known to be associated with Alzheimer's disease (A beta(1-42)) and hereditary cerebral hemorrhage with amyloidosis--Dutch type (A beta(22Q)(1-40)). The vasoactivity appears to be related to the conformation adopted by the peptide in solution. The beta-pleated sheet rich A beta(1-42) and A beta(22Q)(1-40) were each less vasoactive than the mainly random coil wild type A beta(1-40). However, the most vasoactive A beta peptides were combinations which contain mixtures of random coil and beta-sheet structure. The finding that peptides containing low or high levels of beta-pleated conformation are less vasoactive than those containing intermediate amounts of this structural motif allows us to propose the existence of a transitional form between random coil and beta-pleated that is the vasoactive species of A beta. This is the first time that A beta conformational intermediates have been identified and a biological activity associated with them.

Amyloid beta-Peptides↗
PubMed1998

Alzheimer's beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40.

Accumulating evidence suggests that beta-amyloid (Abeta)-induced inflammatory reactions may partially drive the pathogenesis of Alzheimer's disease (AD). Recent data also implicate similar inflammatory processes in cerebral amyloid angiopathy (CAA). To evaluate the roles of Abeta in the inflammatory processes in vascular tissues, we have tested the ability of Abeta to trigger inflammatory responses in cultured human vascular cells. We found that stimulation with Abeta dose-dependently increased the expression of CD40, and secretion of interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) in endothelial cells. Abeta also induced expression of IFN-gamma receptor (IFN-gammaR) both in endothelial and smooth muscle cells. Characterization of the Abeta-induced inflammatory responses in the vascular cells showed that the ligation of CD40 further increased cytokine production and/or the expression of IFN-gammaR. Moreover, IL-1beta and IFN-gamma synergistically increased the Abeta-induced expression of CD40 and IFN-gammaR. We have recently found that Abeta induces expression of adhesion molecules, and that cytokine production and interaction of CD40-CD40 ligand (CD40L) further increase the Abeta-induced expression of adhesion molecules in these same cells. These results suggest that Abeta can function as an inflammatory stimulator to activate vascular cells and induces an auto-amplified inflammatory molecular cascade, through interactions among adhesion molecules, CD40-CD40L and cytokines. Additionally, Abeta1-42, the more pathologic form of Abeta, induces much stronger effects in endothelial cells than in smooth muscle cells, while the reverse is true for Abeta1-40. Collectively, these findings support the hypothesis that the Abeta-induced inflammatory responses in vascular cells may play a significant role in the pathogenesis of CAA and AD.

Alzheimer Disease↗
PubMed1998

The -491A/T apolipoprotein E promoter polymorphism association with Alzheimer's disease: independent risk and linkage disequilibrium with the known APOE polymorphism.

The epsilon4 allele of the apolipoprotein E gene (APOE) has repeatedly been associated with increased risk for Alzheimer's disease (AD). Bullido and colleagues recently identified a polymorphism in the promoter region of the APOE gene (-491A/T) and found that -491A homozygosity predicted AD independently of APOE epsilon4. Since the -491A/T polymorphism and the known APOE polymorphism must be in tight linkage disequilibrium, and the later polymorphism is know to be associated with the disease, we wished to determine to what extent this linkage disequilibrium explained the -491A/T polymorphism association with Alzheimer's disease. We genotyped a community-based control sample (n = 132) and a clinic-based Alzheimer's disease sample (n = 190) for the known APOE and -491A/T polymorphisms, and find that, while the -491A/T polymorphism confers some independent risk for AD, linkage disequilibrium between the known APOE and -491A/T polymorphic sites explains most of the -491A association. Furthermore, when considering the known APOE and -491A/T polymorphisms alone, APOE epsilon4 status is the best predictor of the disease.

Aged↗
PubMed1998

The butyrylcholinesterase gene is neither independently nor synergistically associated with late-onset AD in clinic- and community-based populations.

The K variant of the butyrylcholinesterase gene (BChE) was recently found to occur at an increased frequency in a late onset Alzheimer's disease (AD) population, specifically in individuals carrying the epsilon4 allele of the apolipoprotein E (APOE) gene. This suggested synergy between these two genes resulting in an increased risk of late-onset AD. We have genotyped 62 community-based and 329 clinic-based AD cases, and 201 community-based controls at BChE and APOE and find no independent association between BChE and AD nor interaction with APOE in risk for AD in either our clinic or community-based samples.

Aged↗
PubMed1998

Characteristics of the in vitro vasoactivity of beta-amyloid peptides.

The beta-amyloid (A beta 1-40) peptide has previously been shown to enhance phenylephrine contraction of aortic rings in vitro. We have employed a novel observation, that A beta peptides enhance endothelin-1 (ET-1) contraction, to examine the relationship between vasoactivity and potential amyloidogenicity of A beta peptides, the role played by free radicals and calcium in the vasoactive mechanism, and the requirement of an intact endothelial layer for enhancement of vasoactivity. Rings of rat aortae were constricted with ET-1 before and after addition of amyloid peptide and/or other compounds, and a comparison was made between post- and pre-treatment contractions. In this system, vessel constriction is consistently dramatically enhanced by A beta 1-40, is enhanced less so by A beta 1-42, and is not enhanced by A beta 25-35. The endothelium is not required for A beta vasoactivity, and calcium channel blockers have a greater effect than antioxidants in blocking enhancement of vasoconstriction by A beta peptides. In contrast to A beta-induced cytotoxicity, A beta-induced vasoactivity is immediate, occurs in response to low doses of freshly solubilized peptide, and appears to be inversely related to the amyloidogenic potential of the A beta peptides. We conclude that the mechanism of A beta vasoactivity is distinct from that of A beta cytotoxicity. Although free radicals appear to modulate the vasoactive effects, the lack of requirement for endothelium suggests that loss of the free radical balance (between NO and O2-) may be a secondary influence on A beta enhancement of vasoconstriction. These effects of A beta on isolated vessels, and reported effects of A beta in cells of the vasculature, suggest that A beta-induced disruption of vascular tone may be a factor in the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. Although the mechanism of enhanced vasoconstriction is unknown, it is reasonable to propose that in vivo contact of A beta peptides with small cerebral vessels may increase their tendency to constrict and oppose their tendency to relax. The subclinical ischemia resulting from this would be expected to up-regulate beta APP production in and around the vasculature with further increase in A beta formation and deposition. The disruptive and degenerative effects of such a cycle would lead to the complete destruction of cerebral vessels and consequently neuronal degeneration in the affected areas.

Alzheimer Disease↗
PubMed1998

Role of peroxynitrite in the vasoactive and cytotoxic effects of Alzheimer's beta-amyloid1-40 peptide.

Increasing evidence implicates oxidative stress as partially responsible for the neurodegenerative process of Alzheimer's disease (AD). Recent reports show an increased production of nitrotyrosine in AD brains, suggesting that peroxynitrite is produced in excess in this disease. Furthermore, incidence of cerebral amyloid angiopathy in AD cases is very frequent (83%), strongly suggesting a vascular component of AD pathogenesis. We have evaluated the hypothesis that peroxynitrite could be responsible for mediating the cytotoxicity and vasoactivity induced by the amyloid-beta1-40 (Abeta) peptide. Rat brain endothelial cells (RBE-4) appear to be sensitive to Abeta-induced toxicity but not to the cytotoxicity induced by peroxynitrite. Addition of Cu/Zn superoxide dismutase to cell culture media, which is only able to clear extracellular superoxide, was not effective in blocking Abeta-induced toxicity. However, we were able to partially block Abeta-induced cytotoxicity by using Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP) which dismutes superoxide intracellularily. Yet, MnTBAP was not able to prevent the vasoactivity triggered by Abeta. Moreover, addition of peroxynitrite to rat aortae did not modulate the vasotension induced by Abeta. We conclude that intracellular superoxide radicals may contribute to Abeta-induced cytotoxicity. Our results also indicate that peroxynitrite does not significantly contribute to Abeta-induced cytotoxicity in rat brain endothelial cells (RBE-4) or vasoactivity in rat aortae. These results suggest that therapeutic efforts aimed at removal of reactive oxygen species with SOD is unlikely to be beneficial for treatment of Abeta-induced endothelial dysfunction. However, compounds that clear free radicals intracellularly may well be beneficial.

Alzheimer Disease↗
PubMed1997

The vasoactivity of A beta peptides.

We have demonstrated that freshly solubilized A beta peptides can enhance vasoconstriction by phenylephrine or endothelin of isolated rat aorta. Concentrations of peptide producing these effects (100 nM-1 microM) are much lower than those requiring toxicity to endothelial cells in culture, and effects are immediate, not requiring the prolonged time periods for aggregation necessary in A beta cell culture toxicity experiments. Pre-treatment with SOD diminishes the enhancement of vasoconstriction by A beta peptides, suggesting that the effects are partly mediated via a decrease in the nitric oxide/superoxide ratio. Enhancement of endothelin vasoconstriction is observed with A beta 1-40 and A beta 1-42, but not with A beta 25-35 even at 5 microM, again suggesting the mechanism of A beta vasoactivity is distinct from that of A beta cytotoxicity. These observations raise the possibility that A beta peptides in contact with the cerebrovasculature could result in vasoconstriction, hypoperfusion and oxygen free radical imbalance contributing to the neurodegeneration of AD.

Amyloid beta-Peptides↗
PubMed1997

No association between the low density lipoprotein receptor-related protein (LRP) gene and late-onset Alzheimer's disease in a community-based sample.

It is now commonly known that possession of the epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for both familial and sporadic Alzheimer's disease (AD), in a dose-dependent way. Other genes that may play a role in AD, either through independent association with the disease or through modification of the existing APOE risk, have been reported with conflicting results. One such gene, the low density lipoprotein receptor-related protein (LRP) gene, was recently reported by two groups to be associated with AD, although the groups identified different risk-conferring alleles. Both studies were based on clinic-derived AD populations (one American, one French), and both reported only marginally significant results. We have genotyped a community-based AD and control population at this LRP polymorphism and find no association between the variants at that polymorphism and the occurrence of AD. Further, despite the biochemical relationship between LRP and the ApoE protein, we find no significant statistical interaction between the alleles at these loci.

Age of Onset↗
PubMed1997

APOE is linked to Alzheimer's disease in a large pedigree.

Although previous association studies have demonstrated that the APOE4 allele is a risk factor for Alzheimer's disease (AD), its value for the prediction of AD in individuals is <100%. The limited predictive value of epsilon4 is also seen in multiply affected families where the epsilon4 allele is not tightly linked to AD. We analyzed a large pedigree multiply affected with AD by lod score linkage analysis at the known loci associated with AD. In this pedigree, the APOE/APOCI gene area was linked to the development of AD, while no linkage was detected to any of the other loci known to be associated with the disease. In this family, then, the inheritance of an epsilon4 allele is highly associated with the early development of the disease (mean age of onset, 62 years), and is a good predictor of disease. However, given the wealth of evidence for association, but not linkage, of APOE4 to AD, we believe this finding suggests that another factor (or factors) interact(s) with APOE to precipitate early disease, and produce positive linkage results. The nature of this factor presently remains unknown.

Age of Onset↗
PubMed1997

Superoxide free radical and intracellular calcium mediate A beta(1-42) induced endothelial toxicity.

The 39-42 amino acid residue amyloid beta peptide (A beta), the major protein component in senile plaques and cerebrovascular amyloidosis in the brain in Alzheimer's disease (AD), has been shown to be neurotoxic in vitro. Accumulating data from several areas suggest that cerebrovascular dysfunction and damage may also play a significant role in the AD process. For instance, we have recently demonstrated enhanced vasoconstriction and resistance to relaxation in intact rat aorta treated with A beta [Thomas et al., beta-Amyloid-mediated vasoactivity and vascular endothelial damage, Nature, 380 (1996) 168-171]. Significant vessel damage occurred after thirty minutes of exposure, but could be prevented with superoxide dismutase. To further investigate the role of A beta toxicity on endothelial cells, we have applied A beta peptides to cultures of human aortic endothelial cells (HAEC). Our results show that both A beta(1-42) and A beta(25-35) are toxic to HAEC in a time- and dose-dependent manner, and that this toxicity can be partially prevented by the calcium channel blocker, verapamil, and the antioxidant, superoxide dismutase. The common form of A beta, A beta(1-40), which has been shown to be neurotoxic, is much less toxic to HAEC. A beta toxicity to HAEC occurs within 30 min of treatment with relatively lower doses than those usually observed in primary cultured neurons and vascular smooth muscle cells. It was recently reported that a variety of mutations in the beta-amyloid protein precursor gene and the Presenilin-1 and -2 genes linked to early-onset familial AD cause an increase in the plasma concentration of A beta(1-42) in mutation carriers [Scheuner et al., Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vitro by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Med., 2 (1996) 864-870]. Human aortic endothelial cells are more sensitive to A beta(1-42) than A beta(1-40), via a pathway involving an excess of superoxide free radicals and influx of extracellular calcium. Finally, we have evidence that both apoptotic and necrotic processes are activated by the A beta peptides in these endothelial cells.

Amyloid beta-Peptides↗
PubMed1997

No interaction between the APOE and the alpha-1-antichymotrypsin genes on risk for Alzheimer's disease.

It is now known that possession of one of the three common forms of the apolipoprotein E gene (allele epsilon 4) confers an increased risk for Alzheimer's disease (AD), both familial and sporadic, and that this risk is dose-dependent. Other genes that may play a role in AD, either through independent association with the disease or through modification of, or interaction with, the existing apolipoprotein E (APOE) risk, are now under investigation including the alpha-1-antichymotrypsin (ACT) gene, the very low density lipoprotein receptor (VLDL-R) gene, and the presenilin-1 (PS-1) gene. Kamboh et al. [1995] reported that a polymorphism in the alpha-1-antichymotrypsin gene could modify the risk for AD conferred by the APOE locus, specifically by increasing the risk for AD among epsilon 4 homozygotes. The ACT gene, which is found on chromosome 14, has previously been proposed as a candidate for AD due to the presence of the ACT protein in senile plaques and the reported elevation of the protein in the cerebro-spinal fluid (CSF) and serum of AD cases. We have investigated this reported association within our familial and sporadic AD dataset, where we find no independent association between ACT and the occurrence of AD. Logistic regression analysis excludes ACT or the interaction between ACT and APOE as significant contributors in the prediction of disease status. By this analysis, ACT genotyping does not provide additional information about an individual's risk of Alzheimer's disease beyond the risk information conferred by APOE genotype alone.

Aged↗
PubMed1997

No association between the intronic presenilin-1 polymorphism and Alzheimer's disease in clinic and population-based samples.

Mutations in the Presenilin 1 (PS1) gene on chromosome 14 cause most early-onset familial Alzheimer's disease (AD). An intronic polymorphism in the PS1 gene was recently identified and reported to be associated with late-onset AD [Wragg et al., Lancet 347: 509-512, 1996]. The authors found an excess of homozygotes for the more common allele (allele 1) in AD cases, associated with an approximate doubling of risk. In the present study, we report the PS1 polymorphism distributions in clinic and population-based samples. We were not able to replicate the findings of Wragg et al. [1996]. Our results are consistent with those of other researchers and do not support the conclusion that the PS1 polymorphism is associated with late-onset AD.

Alleles↗
PubMed1997

No association between the very low density lipoprotein receptor gene and late-onset Alzheimer's disease nor interaction with the apolipoprotein E gene in population-based and clinic samples.

It is now commonly known that possession of one of the three common alleles of the apolipoprotein E (APOE) gene (allele epsilon 4) confers an increased risk for both familial and sporadic Alzheimer's disease (AD), and that this risk is dose-dependent. Other genes that may play a role in AD, either through independent association with the disease or through modification of the existing APOE risk, are under investigation. One such gene, the very low density lipoprotein receptor (VLDL-R) gene, was reported by Okuizumi et al. to be independently associated with AD in a Japanese population, but not interactive with the APOE4 conferred risk. Their clinic-based data set demonstrated a 2-fold increased risk conferred by the 5-repeat allele of a polymorphism in VLDL-R. As recruitment from a clinic rather than a population-based sample may result in a distortion of allele frequencies, as has been shown with APOE allele frequencies, it is important to investigate this association in a population-based study. We have genotyped both population and clinic-based AD data sets at this VLDL-R polymorphism, and we find no independent association between the VLDL-R gene and the occurrence of AD in either sample. Further, despite the biochemical relationship between the VLDL-R and APOE proteins, we find no significant statistical interaction between the alleles at these loci.

Age of Onset↗
PubMed1996

Familial and population-based studies of apolipoprotein E and Alzheimer's disease.

The finding of an association between the epsilon 4 allele of the APOE locus and the early expression of late-onset Alzheimer's disease (AD) is robust. However, the estimates of the proportion of AD cases carrying one or more copies of the epsilon 4 allele vary dramatically between studies (highest estimates being 180% of lowest ones). Here we compare the results of association studies in samples drawn from an epidemiologically based study design and samples drawn from families selected for linkage studies. The significant differences between results probably point to the unwitting selection of familial factors other than the APOE locus in the family history positive samples. We conclude that any selection procedure tending to enrich samples for positive family history will also tend to artificially increase APOE epsilon 4 allele frequencies in probands. This is of significance in samples drawn from clinical settings where referral may be influenced by previous known family history. Further work is needed to clarify the nature of the additional factors operating within families. We also report data showing an association between late-onset AD and a polymorphism in an adjacent locus to APOE-the APOCI locus. As no additional risk for AD can be attributed to the APOCI locus, the most likely explanation for the association between AD and APOCI is the disequilibrium between the APOCI and APOE loci. Therefore, there are likely to be other genetic markers in the area that can be used in the same way as APOE as a marker of risk for the disease.

Age of Onset↗
PubMed1996

Dopamine DRD2/Cys311 is not associated with chronic schizophrenia.

A mutation in the DRD2 receptor gene has been reported in association with schizophrenia in Japanese and Caucasian populations. The variation, Ser to Cys at codon 311, occurs in the third intracellular loop of the receptor and is therefore putatively functional. We report the results of screening US Caucasian schizophrenic and nonschizophrenic populations. We detected the occurrence of the DRD2 Cys311 variant in both schizophrenics and controls. Our data demonstrates no significant difference between the frequency of Cys311 in Caucasian schizophrenic and non-schizophrenic populations, indicating no association with schizophrenia.

Asian People↗