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11. Association of Plasma Clusterin Concentration With Severity, Pathology, and Progression in Alzheimer Disease

Author

Thambisetty, Madhav, Simmons, Andrew, Velayudhan, Latha, Hye, Abdul, Campbell, James, Zhang, Yi, Wahlund, Lars-Olof, Westman, Eric, Kinsey, Anna, Güntert, Andreas, Proitsi, Petroula, Powell, John, Causevic, Mirsada, Killick, Richard, Lunnon, Katie, Lynham, Steven, Broadstock, Martin, Choudhry, Fahd, Howlett, David R., Williams, Robert J., Sharp, Sally I., Mitchelmore, Cathy, Tunnard, Catherine, Leung, Rufina, Foy, Catherine, O’Brien, Darragh, Breen, Gerome, Furney, Simon J., Ward, Malcolm, Kloszewska, Iwona, Mecocci, Patrizia, Soininen, Hilkka, Tsolaki, Magda, Vellas, Bruno, Hodges, Angela, Murphy, Declan G., Parkins, Sue, Richardson, Jill C., Resnick, Susan M., Ferrucci, Luigi, Wong, Dean F., Zhou, Yun, Muehlboeck, Sebastian, Evans, Alan, Francis, Paul T., Spenger, Christian, and Lovestone, Simon

Published
2010

12. Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease

Author

Sekhar, Gayathri Nair, primary, Fleckney, Alice L., additional, Boyanova, Sevda Tomova, additional, Rupawala, Huzefa, additional, Lo, Rachel, additional, Wang, Hao, additional, Farag, Doaa B., additional, Rahman, Khondaker Miraz, additional, Broadstock, Martin, additional, Reeves, Suzanne, additional, and Thomas, Sarah Ann, additional

Published
2019
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13. Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia

Author

Alghamdi, Amani, Vallortigara, Julie, Howlett, David R, Broadstock, Martin, Hortobágyi, Tibor, Ballard, Clive, Thomas, Alan J, O'Brien, John T, Aarsland, Dag, Attems, Johannes, Francis, Paul T, Whitfield, David R, O'Brien, John [0000-0002-0837-5080], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, Cerebral Cortex, Lewy Body Disease, Male, Analysis of Variance, Proteasome Endopeptidase Complex, Orvostudományok, Mental Status and Dementia Tests, Klinikai orvostudományok, amyloid-beta, Parkinson’s disease with dementia, Cohort Studies, RPT6, mental disorders, ATPases Associated with Diverse Cellular Activities, Humans, Cognitive Dysfunction, Female, tau, dementia with Lewy bodies, Alzheimer’s disease, ubiquitin proteasome system, cognitive impairment, Aged
Abstract

Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus' cortex were selected as regions of interest from Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p

Published
2017
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15. [P1-235]: RELATIONSHIP BETWEEN PATHOLOGY SCORES, CLINICAL DATA AND EXPRESSION LEVELS OF PROTEASOME SUB-UNITS IN ALZHEIMER's DISEASE AND LEWY BODY DEMENTIAS

Author

Hortobagyi, Tibor, primary, Alghamdi, Amani, additional, Vallortigara, Julie, additional, Whitfield, David, additional, Howlett, David, additional, Broadstock, Martin, additional, Ballard, Clive, additional, Attems, Johannes, additional, Aarsland, Dag, additional, and Francis, Paul T., additional

Published
2017
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16. [P2-204]: RPT6, 20S α-6 AND α-3 PROTEASOME SUBUNIT LEVELS AND ASSOCIATION WITH COGNITIVE DECLINE IN ALZHEIMER's DISEASE AND LEWY BODY DEMENTIAS

Author

Hortobagyi, Tibor, primary, Alghamdi, Amani, additional, Whitfield, David, additional, Vallortigara, Julie, additional, Howlett, David, additional, Broadstock, Martin, additional, Ballard, Clive, additional, Thomas, Alan, additional, Attems, Johannes, additional, Aarsland, Dag, additional, and Francis, Paul T., additional

Published
2017
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17. Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia

Author

Alghamdi, Amani, primary, Vallortigara, Julie, additional, Howlett, David R., additional, Broadstock, Martin, additional, Hortobágyi, Tibor, additional, Ballard, Clive, additional, Thomas, Alan J., additional, O’Brien, John T., additional, Aarsland, Dag, additional, Attems, Johannes, additional, Francis, Paul T., additional, and Whitfield, David R., additional

Published
2017
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18. A genetically immortalized human stem cell line: a promising new tool for Alzheimer's disease therapy

Author

Puangmalai, Nicha, Somani, Alyma, Thangnipon, Wipawan, Ballard, Clive, and Broadstock, Martin

Subjects
neural stem cell, okadaic acid, oligomeric amyloid-ß, CTX0E03 cell line, oligomeric amyloid-β, Original Article, Alzheimer's disease, Alzheimer’s disease, cell viability
Abstract

Amyloid-β peptides and hyper-phosphorylated tau are the main pathological hallmarks of Alzheimer's disease (AD). Given the recent failure of several large-scale clinical trials and the lack of disease-modifying pharmacological treatments, there is an urgent need to develop alternative therapies. A clinical grade human CTX0E03 neural stem cell line has recently passed phase I trials in people with stroke. However, this cell line has not been investigated in other neurodegenerative disorders. This study investigates the survival of CTX0E03 cells under conditions based on the underlying AD pathology. Cell viability assays showed a concentration dependence of this cell line to the toxic effects of Aβ1-42, but not Aβ1-40, and okadaic acid, a phosphatase 2A inhibitor. Notably, CTX0E03 cell line displayed toxicity at concentrations significantly higher than both rat neural stem cells and those previously reported for primary cultures. These results suggest CTX0E03 cells could be developed for clinical trials in AD patients., EXCLI Journal; 14:Doc1135; ISSN 1611-2156

Published
2015

31. A GENETICALLY IMMORTALIZED HUMAN STEM CELL LINE: A PROMISING NEW TOOL FOR ALZHEIMER'S DISEASE THERAPY.

Author

Nicha Puangmalai, Alyma Somani, Wipawan Thangnipon, Ballard, Clive, and Broadstock, Martin

Subjects
STEM cell research, AMYLOID, PEPTIDES, TAU proteins, ALZHEIMER'S disease research
Abstract

Amyloid-β peptides and hyper-phosphorylated tau are the main pathological hallmarks of Alzheimer's disease (AD). Given the recent failure of several large-scale clinical trials and the lack of disease-modifying pharmacological treatments, there is an urgent need to develop alternative therapies. A clinical grade human CTX0E03 neural stem cell line has recently passed phase I trials in people with stroke. However, this cell line has not been investigated in other neurodegenerative disorders. This study investigates the survival of CTX0E03 cells under conditions based on the underlying AD pathology. Cell viability assays showed a concentration dependence of this cell line to the toxic effects of Aβ1-42, but not Aβ1-40, and okadaic acid, a phosphatase 2A inhibitor. Notably, CTX0E03 cell line displayed toxicity at concentrations significantly higher than both rat neural stem cells and those previously reported for primary cultures. These results suggest CTX0E03 cells could be developed for clinical trials in AD patients. [ABSTRACT FROM AUTHOR]

Published
2015
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36. The unfolded protein response : a potential link between heterozygous mutations in GBA1 and Lewy body dementia?

Author

Clarke, Emily Jayne, Broadstock, Martin, and Francis, Paul Thomas

Subjects
616.8
Abstract

Lewy body dementia (LBD) is characterised by the deposition of a-synuclein containing Lewy bodies throughout cortical brain regions. Pathology is confounded by the co-occurrence of pathological Ab and tau deposition. LBD comprises dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), distinguished by the timing of onset of classical symptoms: cognitive impairment occurs at least one year prior to motor impairment in DLB and vice versa in PDD. Currently, there are no disease modifying therapeutic agents for LBD. Heterozygous mutations in GBA1 have become established as the most common genetic risk factor for Parkinson’s disease and dementia with Lewy bodies. GBA1 encodes the lysosomal enzyme glucocerebrosidase. Deficient glucocerebrosidase activity causes accumulation of a-synuclein. Homozygous GBA1 mutation causes the lysosomal storage disorder Gaucher’s disease. In this thesis, a possible mechanism underlying the link between GBA1 mutation and LBD is investigated - the unfolded protein response (UPR). We hypothesise that the UPR is activated in response to mutant GBA1 but is unable to serve a protective function under increasing levels of stress. We also characterise the impact of heterozygous GBA1 mutation (D427V) on mice to establish whether a cognitive impairment phenotype is displayed which may be translational for the study of LBD. The results presented in this thesis support the activation of both IRE1a and PERK mediated UPR responses since we show increased expression of spliced XBP1 and CHOP in a L444P mutant GBA1 SH-SY5Y cell model. We also demonstrate spliced XBP1 ceases to be expressed under increasing cellular stress whilst CHOP expression continues. Since CHOP is associated with detrimental cell outcomes, predominantly initiation of apoptosis, we suggest that the imbalance of UPR responses towards CHOP mediated effects may potentially underlie pathological consequences associated with GBA1 mutation. Results presented in this thesis also reveal a previously unreported progressive cognitive decline in D427V/WT GBA1 mice. In conclusion, preventing the withdrawal of protective spliced XBP1 mediated effects and continued expression CHOP may be a therapeutic avenue for further investigation in D427V/WT GBA1 mice which show promising signs of being a translational model for LBD.

Published
2018

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