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Your search keyword '"Schmechel, D.E."' showing total 38 results
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38 results on '"Schmechel, D.E."'

1. Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration

Author

Malek, G., Johnson, L.V., Mace, B.E., Saloupis, P., Schmechel, D.E., Rickman, D.W., Toth, C.A., Sullivan, P.M., and Rickman, C. Bowes

Subjects
Macular degeneration -- Risk factors, Macular degeneration -- Care and treatment, Aged -- Diseases, Alzheimer's disease -- Care and treatment, Science and technology
Abstract

Age-related macular degeneration (AMD) is a late-onset, multifactorial, neurodegenerative disease of the retina and the leading cause of irreversible vision loss in the elderly in the Western world. We describe here a murine model that combines three known AMD risk factors: advanced age, high fat cholesterol-rich (HF-C) diet, and apolipoprotein E (apoE) genotype. Eyes of aged, targeted replacement mice expressing human apoE2, apoE3, or apoE4 and maintained on a HF-C diet show apoE isoform-dependent pathologies of differential severity. ApoE4 mice are the most severely affected. They develop a constellation of changes that mimic the pathology associated with human AMD. These alterations include diffuse sub-retinal pigment epithelial deposits, drusenoid deposits, thickened Bruch's membrane, and atrophy, hypopigmentation, and hyperpigmentation of the retinal pigment epithelium. In extreme cases, apoE4 mice also develop marked choroidal neovascularization, a hallmark of exudative AMD. Neither age nor HF-C diet alone is sufficient to elicit these changes. We document choroidal neovascularization and other AMD-like ocular pathologies in an animal model that exploits known AMD risk factors. The model is additionally attractive because it is not complicated by invasive experimental intervention. Our findings in this model implicate the human apoE E4 allele as a susceptibility gene for AMD and support the hypothesis that common pathogenic mechanisms may underlie AMD and Alzheimer's disease. amyloid | choroidal neovascularization | macula | retinal pigment epithelium | cholesterol

Published
2005

4. Interaction between the (alpha)-T catenin gene (VR22) and APOE in Alzheimer's disease

Author

Martin, E.R., Bronson, P.G., Li, Y.-J., Wall, N., Chung, R.-H., Schmechel, D.E., Small, G., Xu, P.-T., Bartlett, J., Schnetz-Boutaud, N., Haines, J.L., Gilbert, J.R., and Pericak-Vance, M.A.

Subjects
Alzheimer's disease -- Genetic aspects, Alzheimer's disease -- Causes of, Single nucleotide polymorphisms -- Research, Apolipoproteins -- Analysis, Genetic susceptibility -- Research, Health
Published
2005

5. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease

Author

Schmechel, D.E., Saunders, A.M., Strittmatter, W.J., Crain, B.J., Hulette, C.M., Joo, S.H., Pericak-Vance, M.A., Goldgaber, D., and Roses, A.D.

Subjects
Peptides -- Research, Apolipoproteins -- Analysis, Genotype -- Analysis, Science and technology
Abstract

Routine neuropathological reports, and analyses of Congo red- and immunostained slides are used to investigate the level of amyloid deposition in autopsy-confirmed incidents of sporadic late-onset Alzheimer disease (AD) in patients with defined apolipoprotein E genotype (APOE), to determine if the APOE genotype can be related to a characteristic neuropathological phenotype. A characteristic neuropathological phenotype of significantly enhanced vascular and plaque amyloid beta-peptide deposits compared with patients homozygous for APOE3 is evident in those with sporadic late-onset AD.

Published
1993

8. Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease

Author

Li, Y-J, Oliveira, S.A., Puting, X., Martin, E.R., Stenger, J.E., Hulette, C., Scherzer, C.R., Hauser, M.A., Scott, W.K., Small, G.W., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Goetz, C.G., Mastaglia, F., Middleton, L.T., Roses, A.D., Saunders, A.M., Welsh-Bohmer, K.A., Schmechel, D.E., Gullans, S.R., Haines, J.L., Gilbert, J.R., Vance, J.M., Pericak-Vance, M.A., Li, Y-J, Oliveira, S.A., Puting, X., Martin, E.R., Stenger, J.E., Hulette, C., Scherzer, C.R., Hauser, M.A., Scott, W.K., Small, G.W., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Goetz, C.G., Mastaglia, F., Middleton, L.T., Roses, A.D., Saunders, A.M., Welsh-Bohmer, K.A., Schmechel, D.E., Gullans, S.R., Haines, J.L., Gilbert, J.R., Vance, J.M., and Pericak-Vance, M.A.

Abstract

Erratum

Published
2004

9. Glutathione S-transferase omega-1 modifiesage-at-onset of Alzheimer disease and Parkinson disease

Author

Li, Y-J, Oliveira, S.A., Xu, P., Martin, E.R., Stenger, J.E., Scherzer, C.R., Hauser, M.A., Scott, W.K., Small, G.W., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Goetz, C.G., Mastaglia, F., Middleton, L.T., Roses, A.D., Saunders, A.M., Schmechel, D.E., Gullans, S.R., Haines, J.L., Gilbert, J.R., Vance, J.M., Pericak-Vance, M.A., Li, Y-J, Oliveira, S.A., Xu, P., Martin, E.R., Stenger, J.E., Scherzer, C.R., Hauser, M.A., Scott, W.K., Small, G.W., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Goetz, C.G., Mastaglia, F., Middleton, L.T., Roses, A.D., Saunders, A.M., Schmechel, D.E., Gullans, S.R., Haines, J.L., Gilbert, J.R., Vance, J.M., and Pericak-Vance, M.A.

Abstract

We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of ‘genomic convergence’ to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine interleukin-1β. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.

Published
2003

10. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease

Author

van der Walt, J.M., Nicodemus, K.K., Martin, E.R., Scott, W.K., Nance, M.A., Watts, R.L., Hubble, J.P., Haines, J.L., Koller, W.C., Lyons, K., Pahwa, R., Stern, M.B., Colcher, A., Hiner, B.C., Jankovic, J., Ondo, W.G., Allen Jr., F.H., Goetz, C.G., Small, G.W., Mastaglia, F., Stajich, J.M., McLaurin, A.C., Middleton, L.T., Scott, B.L., Schmechel, D.E., Pericak-Vance, M.A., Vance, J.M., van der Walt, J.M., Nicodemus, K.K., Martin, E.R., Scott, W.K., Nance, M.A., Watts, R.L., Hubble, J.P., Haines, J.L., Koller, W.C., Lyons, K., Pahwa, R., Stern, M.B., Colcher, A., Hiner, B.C., Jankovic, J., Ondo, W.G., Allen Jr., F.H., Goetz, C.G., Small, G.W., Mastaglia, F., Stajich, J.M., McLaurin, A.C., Middleton, L.T., Scott, B.L., Schmechel, D.E., Pericak-Vance, M.A., and Vance, J.M.

Abstract

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34–0.91; P=.02) or K (OR 0.52; 95% CI 0.30–0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39–0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27–0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22–0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.

Published
2003

11. Age at onset in two common neurodegenerative diseases is genetically controlled

Author

Li, Y-J, Scott, W.K., Hedges, D.J., Zhang, F., Gaskell, P.C., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Allen, F.H., Goetz, C.G., Mastaglia, F., Stajich, J.M., Gibson, R.A., Middleton, L.T., Saunders, A.M., Scott, B.L., Small, G.W., Nicodemus, K.K., Reed, A.D., Schmechel, D.E., Welsh-Bohmer, K.A., Conneally, P.M., Roses, A.D., Gilbert, J.R., Vance, J.M., Haines, J.L., Pericak-Vance, M.A., Li, Y-J, Scott, W.K., Hedges, D.J., Zhang, F., Gaskell, P.C., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C., Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Allen, F.H., Goetz, C.G., Mastaglia, F., Stajich, J.M., Gibson, R.A., Middleton, L.T., Saunders, A.M., Scott, B.L., Small, G.W., Nicodemus, K.K., Reed, A.D., Schmechel, D.E., Welsh-Bohmer, K.A., Conneally, P.M., Roses, A.D., Gilbert, J.R., Vance, J.M., Haines, J.L., and Pericak-Vance, M.A.

Abstract

To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%–60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases.

Published
2002

12. Longitudinal follow‐up of late‐onset Alzheimer disease families

Author

Carney, R.M., primary, Slifer, M.A., additional, Lin, P.I., additional, Gaskell, P.C., additional, Scott, W.K., additional, Potocky, C.F., additional, Hulette, C.M., additional, Welsh‐Bohmer, K.A., additional, Schmechel, D.E., additional, Vance, J.M., additional, and Pericak‐Vance, M.A., additional

Published
2008
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16. Apolipoprotein E-e4 and apolipoprotein E-e2 are susceptibility genes that affect the rate of disease expressivity of late-onset familial and sporadic Alzheimer disease

Author

Roses, A.D., primary, Saunders, A.M., additional, Corder, E.H., additional, Risch, N.J., additional, Haines, J.L., additional, Pericak-Vance, M.A., additional, Han, S.-H., additional, Einstein, G., additional, Hulette, C., additional, Schmechel, D.E., additional, Goedert, M., additional, Jakes, R., additional, Dong, L.-M., additional, Weisgraber, K.H., additional, Holsti, M., additional, Huang, D., additional, and Strittmatter, W.J., additional

Published
1994
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17. Apolipoprotein E ∈4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases

Author

Saunders, A.M, primary, Roses, A.D, additional, Pericak-Vance, M.A, additional, Dole, K.C, additional, Strittmatter, W.J, additional, Schmechel, D.E, additional, Szymanski, M.H, additional, McCown, N, additional, Manwaring, M.G, additional, Schmader, K, additional, Breitner, J.C.S, additional, Goldgaber, D, additional, Benson, M.D, additional, Goldfarb, L, additional, and Brown, W.T, additional

Published
1993
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18. Regulation and genetic control of brain amyloid

Author

Gajdusek, D.Carleton, primary, Beyreuther, Konrad, additional, Brown, Paul, additional, Cork, Linda C., additional, Cunningham, Dennis D., additional, Frangione, Blas, additional, Gibbs, C.J., additional, Goldfarb, Lev G., additional, Goldgaber, D., additional, Hsiao, Karen K., additional, Koo, Edward H., additional, Martin, Lee J., additional, Masters, Colin L., additional, Odenwald, W.F., additional, Price, Donald L., additional, Prusiner, S.B., additional, Ruddle, Frank H., additional, Safar, Jiri, additional, Scangos, George, additional, Schmechel, D.E., additional, Shashikant, Cooduvalli S., additional, Shlichta, Paul J., additional, Sisodia, Sangram S., additional, Trapp, Bruce D., additional, Unterbeck, Axel, additional, Van Nostrand, William E., additional, Violette, Shelia M., additional, Walker, Lary C., additional, and Wirak, Dana, additional

Published
1991
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19. PfiesteriaToxin and Learning Performance

Author

Levin, E.D, Simon, B.B, Schmechel, D.E, Glasgow, H.B, Deamer-Melia, N.J, Burkholder, J.M, Moser, V.C, Jensen, K, and Harry, G.J

Abstract

Pfiesteria piscicidais an estuarine dinoflagellate involved with fish kills along the east coast of the United States. We previously documented a radial-arm maze learning deficit in rats exposed to Pfiesteriathat may be related to cognitive deficits seen in humans after accidental Pfiesteriaexposure. The current study elucidated important behavioral parameters of this deficit. There were six dose groups. Forty (10/group) adult female Sprague–Dawley rats were injected (SC) with a single dose of Pfiesteriataken from aquarium-cultured Pfiesteria(35,600, 106,800, or 320,400 Pfiesteriacells/kg of rat body weight or a cell-free filtrate of the 106,800 cells/kg dose). One control group (N= 10) was injected with saline and one (N= 10) with aquarium water not containing Pfiesteria.Half of the rats in each group were tested on an 8-arm radial maze in a standard test room, and the other half were tested on the radial maze in a sound-attenuating chamber. In the standard maze room, there was a significant effect of Pfiesteria(p< 0.05) impairing choice accuracy improvement over the first six sessions of training among rats administered 106,800, 320,400, and the 106,800 cells/kg filtered sample. In contrast, there was no indication of an effect of Pfiesteriawhen the rats were tested on the same configuration radial maze in the sound-attenuating chamber. After 18 sessions of training in one room, the rats were switched for six sessions of testing in the other room and finally were switched back to their original room for three sessions. There was a significant Pfiesteria-induced deficit when the rats were tested in the standard test room but not when they were tested in the sound-attenuating chamber. When the Pfiesteria-exposed rats were initially switched from the sound-attenuating chamber to the standard test room they performed significantly worse than controls, whereas Pfiesteria-treated rats switched from the standard test room to the sound-attenuating chamber did not perform differently from controls. These results suggest that the Pfiesteria-induced learning impairment may result from the negative impact of distracting stimuli. At the time of the learning impairment, no overt Pfiesteria-related effects were seen using a functional observational battery and no overall response latency effects were seen, indicating that the Pfiesteria-induced choice accuracy deficit was not due to generalized debilitation. In the initial use of the figure-8 maze in this line of research, the rats in the same Pfiesteriatreatment groups that showed significant deficits in the radial-arm maze showed greater declines in activity rates in a 1-h figure-8 locomotor activity test. Both the 106,800 and 320,400 Pfiesteriacells/kg groups showed significantly greater linear trends of activity decline relative to tank water-treated controls. This reflected an initial slight hyperactivity in the Pfiesteria-treated animals followed by a decrease to control levels. Pfiesteriaeffects in the figure-8 maze and in early radial-arm maze training may be useful in a rapid screen for identifying the critical toxin(s) of Pfiesteriain future studies. Published by Elsevier Science Inc.

Published
1999
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36. Neuropathological Features of Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17q21-22 (FTDP-17): Duke Family 1684

Author

Hulette, C.M., Pericak-Vance, M.A., Roses, A.D., Schmechel, D.E., Yamaoka, L.H., Gaskell, P.C., Welsh-Bohmer, K.A., Crowther, R.A., and Spillantini, M.G.

Abstract

Frontotemporal dementia with parkinsonism (FTDP-17) is an autosomal dominant disorder that presents clinically with dementia, extrapyramidal signs, and behavioral disturbances in mid-life and progresses to death within 5 to 10 years. Pathologically, the disorder is characterized by variable neuronal loss and gliosis in the frontal and temporal lobes, limbic structures, and the midbrain. Autopsied individuals from some kindreds display abundant neurofibrillary change while others, including a single affected individual from Duke Family 1684, lack distinctive histological features and exhibit only mild neuronal loss and gliosis in limbic structures and subcortical nuclei when examined by routine silver stain. Recently, mutations in the microtubule associated protein tau have been shown to segregate with the disease in this family and in many other affected kindreds. In order to examine the distribution of tau deposits, we performed tau immunohistochemistry, immunoblotting, and immunoelectron microscopy of tau-containing filaments. Immunohistochemistry revealed numerous tau deposits within glial cells and within neurons. Twisted ribbon-like filaments observed by immunoelectron microscopy were immunodecorated with tau AT8 antibody. Sarkosyl-insoluble tau extracted from the hippocampus and cortex migrated as 2 major bands at 64 and 68 kilodaltons and a minor band at 72 kilodaltons, which after alkaline phosphatase treatment appeared to contain mainly tau isoforms with 4 repeats. Furthermore, the ratio of soluble tau with 4 to 3 microtubule-binding repeats was increased. The role of tau mutations in this disorder is discussed in this paper.

Published
1999
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