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George Perry – One of the best experts on this subject based on the ideXlab platform.

  • Increased Expression of p130 in Alzheimer Disease
    Neurochemical Research, 2007
    Co-Authors: Laura A. Previll, Meredith E. Crosby, Rudy J. Castellani, Robert Bowser, George Perry, Mark A. Smith, Xiongwei Zhu
    Abstract:

    A number of recent findings support the notion of mechanistic parallels between Alzheimer Disease (AD) and oncogenic processes, specifically, that neurons in AD, like cancer cells, display aberrant mitotic cell cycle re-entry. However, the mechanism that drives postmitotic neurons to reenter cell cycle remains elusive. In this study, we focused on the retinoblastoma-related protein p130 in AD. p130 is a transcriptional regulator that complexes with E2F4/5 in the nucleus and suppresses genes that regulate entry into the cell cycle. Interestingly, our results show that there are increases in p130 in cytoplasm of susceptible pyramidal neurons as well as neuroglia, often surrounding senile plaques, and within Hirano bodies in AD. By marked contrast, p130 is found at background levels in non-Diseased, age-matched controls. Our data suggest that, despite its upregulation, the aberrant localization of p130 to the neuronal cytoplasm facilitates neuronal cell cycle re-entry in AD.

  • Protein Disulfide Isomerase in Alzheimer Disease
    Antioxidants & redox signaling, 2000
    Co-Authors: Hyoun T. Kim, Xiongwei Zhu, Mark A. Smith, Robert L. Russell, Arun K. Raina, Peggy L.r. Harris, Sandra L. Siedlak, Robert B. Petersen, Shun Shimohama, George Perry
    Abstract:

    There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer Disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphosphateydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the Disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI i…

  • Protein Disulfide Isomerase in Alzheimer Disease
    Antioxidants & redox signaling, 2000
    Co-Authors: Hyoun T. Kim, Xiongwei Zhu, Mark A. Smith, Robert L. Russell, Arun K. Raina, Peggy L.r. Harris, Sandra L. Siedlak, Robert B. Petersen, Shun Shimohama, George Perry
    Abstract:

    There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer Disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphosphateydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the Disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.

John C. Morris – One of the best experts on this subject based on the ideXlab platform.

  • Association and Expression Analyses With Single-Nucleotide Polymorphisms in TOMM40 in Alzheimer Disease
    Archives of neurology, 2011
    Co-Authors: Carlos Cruchaga, Petra Nowotny, John S. K. Kauwe, Perry G. Ridge, Kevin H. Mayo, Sarah Bertelsen, Anthony L. Hinrichs, Anne M. Fagan, David M. Holtzman, John C. Morris
    Abstract:

    Background Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer Disease (LOAD). The linkage disedisequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene. Objective To attempt to replicate a recently reported association of APOE 3–TOMM40 haplotypes with risk and age at onset. Design We used standard techniques to genotype several polymorphisms in the APOE–TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue. Setting Alzheimer‘s Disease Research Center. Participants Research volunteers who were cognitively normal or had Alzheimer Disease. Main Outcome Measures Disease status and age at onset. Results We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or β-amyloid 42 levels or TOMM40 or APOE gene expression. Conclusions Although we did not replicate the earlier association between the APOE 3–TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.

  • 11c pib in a nondemented population potential antecedent marker of Alzheimer Disease
    Neurology, 2006
    Co-Authors: Mark A Mintun, William E. Klunk, Gina N Larossa, Yvette I Sheline, Carmen S Dence, S Y Lee, Robert H Mach, Chester A Mathis, Steven T Dekosky, John C. Morris
    Abstract:

    Background: Beta-amyloid (Aβ) plaques are the hallmark of Alzheimer Disease (AD). A PET imaging tracer that binds to Aβ plaques in vivo, N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (or [11C]PIB for “Pittsburgh Compound-B”), has significantly higher binding in subjects diagnosed with dementia of the Alzheimer type (DAT) compared to nondemented controls. The authors used this imaging technique to investigate whether abnormal binding occurs in clinically normal individuals, prior to the development of cognitive changes. Methods: Forty-one nondemented subjects (age range 20 to 86 years) and 10 patients with DAT (age range 66 to 86 years) underwent [11C]PIB PET scanning. Regions of interest were drawn on the MRI over the cerebellar, prefrontal, lateral temporal, occipital, gyrus rectus, precuneus, and striatal cortex. Binding potential values (BPs), proportional to the density of [11C]PIB-Aβ binding sites, were calculated using the Logan graphical analysis and the cerebellar cortex for a reference tissue. Results: Patients with DAT had elevated BP values vs nondemented subjects (p Conclusions: Elevated [11C]PIB binding in nondemented subjects suggests that [11C]PIB amyloid imaging may be sensitive for detection of a preclinical Alzheimer Disease state. Longitudinal studies will be required to determine the association of elevated [11C]PIB binding and risk of developing dementia of the Alzheimer type.

  • Increased neocortical neurofibrillary tangle density in subjects with Alzheimer Disease and psychosis.
    Archives of general psychiatry, 2000
    Co-Authors: Nuri B. Farber, John C. Morris, Eugene H. Rubin, John W. Newcomer, Dorothy A. Kinscherf, J. Philip Miller, John W. Olney, Daniel W. Mckeel
    Abstract:

    Psychosis is common in patients with Alzheimer Disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer Disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer Disease and psychosis had a greater neurofibrillary tangle or senile plaqplaque burden than subjects with Alzheimer Disease and no psychosis. One hundred nine subjects with Alzheimer Disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. Psychosis occurred commonly in Alzheimer Disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer Disease may regulate both phenomena. Arch Gen Psychiatry. 2000;57:1165-1173.

Daniel W. Mckeel – One of the best experts on this subject based on the ideXlab platform.

  • Increased neocortical neurofibrillary tangle density in subjects with Alzheimer Disease and psychosis.
    Archives of general psychiatry, 2000
    Co-Authors: Nuri B. Farber, John C. Morris, Eugene H. Rubin, John W. Newcomer, Dorothy A. Kinscherf, J. Philip Miller, John W. Olney, Daniel W. Mckeel
    Abstract:

    Psychosis is common in patients with Alzheimer Disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer Disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer Disease and psychosis had a greater neurofibrillary tangle or senile plaque burden than subjects with Alzheimer Disease and no psychosis. One hundred nine subjects with Alzheimer Disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. Psychosis occurred commonly in Alzheimer Disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer Disease may regulate both phenomena. Arch Gen Psychiatry. 2000;57:1165-1173.

  • increased neocortical neurofibrillary tangle density in subjects with Alzheimer Disease and psychosis
    Archives of General Psychiatry, 2000
    Co-Authors: Nuri B. Farber, John C. Morris, Eugene H. Rubin, John W. Newcomer, Dorothy A. Kinscherf, John W. Olney, Philip J Miller, Daniel W. Mckeel
    Abstract:

    Background Psychosis is common in patients with Alzheimer Disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer Disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer Disease and psychosis had a greater neurofibrillary tangle or senile plaqplaque burden than subjects with Alzheimer Disease and no psychosis. Methods One hundred nine subjects with Alzheimer Disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. Results Psychosis occured commonly in Alzheimer Disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. Conclusions The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer Disease may regulate both phenomena.

Xiongwei Zhu – One of the best experts on this subject based on the ideXlab platform.

  • Increased Expression of p130 in Alzheimer Disease
    Neurochemical Research, 2007
    Co-Authors: Laura A. Previll, Meredith E. Crosby, Rudy J. Castellani, Robert Bowser, George Perry, Mark A. Smith, Xiongwei Zhu
    Abstract:

    A number of recent findings support the notion of mechanistic parallels between Alzheimer Disease (AD) and oncogenic processes, specifically, that neurons in AD, like cancer cells, display aberrant mitotic cell cycle re-entry. However, the mechanism that drives postmitotic neurons to reenter cell cycle remains elusive. In this study, we focused on the retinoblastoma-related protein p130 in AD. p130 is a transcriptional regulator that complexes with E2F4/5 in the nucleus and suppresses genes that regulate entry into the cell cycle. Interestingly, our results show that there are increases in p130 in cytoplasm of susceptible pyramidal neurons as well as neuroglia, often surrounding senile plaques, and within Hirano bodies in AD. By marked contrast, p130 is found at background levels in non-Diseased, age-matched controls. Our data suggest that, despite its upregulation, the aberrant localization of p130 to the neuronal cytoplasm facilitates neuronal cell cycle re-entry in AD.

  • Protein Disulfide Isomerase in Alzheimer Disease
    Antioxidants & redox signaling, 2000
    Co-Authors: Hyoun T. Kim, Xiongwei Zhu, Mark A. Smith, Robert L. Russell, Arun K. Raina, Peggy L.r. Harris, Sandra L. Siedlak, Robert B. Petersen, Shun Shimohama, George Perry
    Abstract:

    There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer Disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the Disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI i…

  • Protein Disulfide Isomerase in Alzheimer Disease
    Antioxidants & redox signaling, 2000
    Co-Authors: Hyoun T. Kim, Xiongwei Zhu, Mark A. Smith, Robert L. Russell, Arun K. Raina, Peggy L.r. Harris, Sandra L. Siedlak, Robert B. Petersen, Shun Shimohama, George Perry
    Abstract:

    There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer Disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the Disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.

Hyoun T. Kim – One of the best experts on this subject based on the ideXlab platform.

  • Protein Disulfide Isomerase in Alzheimer Disease
    Antioxidants & redox signaling, 2000
    Co-Authors: Hyoun T. Kim, Xiongwei Zhu, Mark A. Smith, Robert L. Russell, Arun K. Raina, Peggy L.r. Harris, Sandra L. Siedlak, Robert B. Petersen, Shun Shimohama, George Perry
    Abstract:

    There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer Disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the Disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI i…

  • Protein Disulfide Isomerase in Alzheimer Disease
    Antioxidants & redox signaling, 2000
    Co-Authors: Hyoun T. Kim, Xiongwei Zhu, Mark A. Smith, Robert L. Russell, Arun K. Raina, Peggy L.r. Harris, Sandra L. Siedlak, Robert B. Petersen, Shun Shimohama, George Perry
    Abstract:

    There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer Disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the Disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.