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T Town

Publications and source records attributed to T Town.

29 records · Page 2Linked to original sources
PubMed1999

The alpha-2 macroglobulin gene is not associated with Alzheimer's disease in a case-control sample.

Genetic association has recently been reported between alleles in the alpha-2-macroglobulin (A2M) gene and the occurrence of Alzheimer's disease (AD) in familial and sporadic samples. We have investigated the A2M intronic deletion polymorphism in a case-control study of 295 unrelated clinic and community-based AD cases, and compared these to a sample of 113 unrelated control individuals recruited as part of an epidemiological study. Our results show no association between A2M and AD in either case sample. Furthermore, A2M is not predictive of AD in an interactive fashion when considering APOE, race or gender. In a subset of our larger sample we have also investigated the A2M Val1000lle polymorphism, and again find no evidence for association. We conclude that there is no genetic association between A2M and AD in our case-control sample.

Aged↗
PubMed1999

Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis.

It is well known that microglial cells perform a key role in mediating inflammatory processes, which are associated with neurodegenerative diseases such as multiple sclerosis (MS). In this study, we report that CD40 expression on microglia is greatly enhanced by a low dose (10 U/ml) of IFN-gamma. We also find that ligation of microglial CD40 by CD40L triggers a significant production of TNF-alpha. Activation of microglia by ligation of CD40 in the presence of IFN-gamma results in cultured cortical neuronal injury, which is markedly attenuated by blockade of the CD40 pathway or neutralization of TNF-alpha. Finally, we find significant levels of IFN-gamma and TNF-alpha in the medium of co-cultured activated CD4+ T cells and microglial cells, showing that microglia can supply the CD40 receptor to activated CD4+ T cells and suggesting that this cellular interaction is a key event in MS pathophysiology.

Animals↗
PubMed1999

No genetic association between polymorphisms in the Tau gene and Alzheimer's disease in clinic or population based samples.

Mutations in the tau protein gene have recently been found to cause familial fronto-temporal dementia in a number of kindreds demonstrating linkage to chromosome 17. Given that tau pathology is a hallmark of Alzheimer's disease (AD), this raises the possibility that mutations in tau may also be associated with AD. We have investigated the allelic frequencies of polymorphisms in the Tau gene for a possible allelic distortion in Alzheimer's cases, which might suggest a conferred genetic risk. We have genotyped 65 community-based and 200 clinic-based AD cases, and 142 community-based controls at the Tau exon 6 AflIII and BslI polymorphisms and find no independent association with risk for AD in these samples. Further analysis including APOE genotypes from the same samples demonstrated no interaction between either of these polymorphisms and APOE in conferring risk for AD. In addition, haplotype analysis across both sites revealed no difference in haplotype frequencies between cases and controls, nor any interaction with APOE. Therefore our data do not suggest any association between these variations in the Tau gene and Alzheimer's disease.

Age of Onset↗
PubMed1999

Inhibition of Alzheimer's beta-amyloid induced vasoactivity and proinflammatory response in microglia by a cGMP-dependent mechanism.

beta-amyloid (Abeta) peptides are the major protein components of senile plaques in Alzheimer's disease (AD) brains. Vascular damage and reactive gliosis are found colocalized with amyloid deposits in AD brains, suggesting that the vasculature may be a clinically significant site of AD pathology. Our results show that freshly solubilized Abeta1-40 enhances the vasoconstriction induced by endothelin-1 (ET-1) and increases resistance to relaxation triggered by nitric oxide (NO), suggesting that Abeta may oppose the NO/cGMP pathway. Using specific inhibitors and activators of the NO/cGMP pathway, we show that Abeta vasoactivity is not due to a modulation of nitric oxide synthase (NOS) or soluble guanylyl cyclase (sGC). However, we find that a selective cGMP phosphodiesterase (cGMP-PDE) inhibitor (dipyridamole) is able to interactively block the enhanced vasoconstriction as well as the opposition to relaxation induced by Abeta, suggesting that Abeta could effect the activity of this enzyme. Cyclic GMP levels, but not cAMP concentrations, are reduced after Abeta treatment of rat aortic rings, further substantiating this hypothesis. Moreover, in examination of this pathway in another cell type pertinent to AD, we find that Abeta induces a proinflammatory response in microglia as evidenced by increased leukotriene B4 release. We show that both dipyridamole and compounds which increase cGMP levels prevent Abeta-induced microglial inflammation. Our results suggest that therapeutic intervention aimed at reduction of microglial-mediated inflammation via inhibition of cGMP-PDE or elevation of cGMP may be beneficial in the treatment of AD.

Alzheimer Disease↗
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

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

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

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↗
PubMedDate not supplied

CD40 signaling and Alzheimer's disease pathogenesis.

The interaction between CD40 and its cognate ligand, CD40 ligand, is a primary regulator of the peripheral immune response, including modulation of T lymphocyte activation, B lymphocyte differentiation and antibody secretion, and innate immune cell activation, maturation, and survival. Recently, we and others have identified CD40 expression on a variety of CNS cells, including endothelial cells, smooth muscle cells, astroglia and microglia, and have found that, on many of these cells, CD40 expression is enhanced by pro-inflammatory stimuli. Importantly, the CD40-CD40 ligand interaction on microglia triggers a series of intracellular signaling events that are discussed, beginning with Src-family kinase activation and culminating in microglial activation as evidenced by tumor necrosis factor-alpha secretion. Based on the involvement of microglial activation and brain inflammation in Alzheimer's disease pathogenesis, we have investigated co-stimulation of microglia, smooth muscle, and endothelial cells with CD40 ligand in the presence of low doses of freshly solubilized amyloid-beta peptides. Data reviewed herein show that CD40 ligand and amyloid-beta act synergistically to promote pro-inflammatory responses by these cells, including secretion of interleukin-1 beta by endothelial cells and tumor necrosis factor-alpha by microglia. As these cytokines have been implicated in neuronal injury, a comprehensive model of pro-inflammatory CD40 ligand and amyloid-beta initiated Alzheimer's disease pathogenesis (mediated by multiple CNS cells) is proposed.

Alzheimer Disease↗
PubMedDate not supplied

Soluble beta-amyloid peptides mediate vasoactivity via activation of a pro-inflammatory pathway.

Freshly solubilized beta-amyloid (Abeta) peptides display vasoactive properties, increasing both the magnitude and the duration of endothelin-1-induced vasoconstriction. We show that Abeta vasoactivity is mediated by the stimulation of a pro-inflammatory pathway involving activation of secretory phospholipase A(2) (PLA(2)), mitogen activated protein kinase (MAPK) kinase (MEK1/2), p38 MAPK, cytosolic PLA(2), and the release of arachidonic acid. Ultimately, arachidonic acid is metabolized into proinflammatory eicosanoids via the 5-lipoxygenase and cyclooxygenase-2 (COX-2) enzymes, both of which we show to be required for A beta vasoactivity. Accordingly, p38 MAPK activity is higher in the brains of transgenic mice that overproduce A beta, and COX-2 immunoreactivity is increased in the cerebrovasculature of these transgenic animals. Taken together, our data show that freshly solubilized A beta peptides can trigger a pro-inflammatory reaction in the vasculature that can be blocked by inhibiting specific target molecules, providing the basis for novel therapeutic intervention.

Amyloid beta-Peptides↗