Search

Your search keyword '"Hooper, Claudie"' showing total 3 results
Start Over Author "Hooper, Claudie" Publication Type Electronic Resources
3 results on '"Hooper, Claudie"'

1. Microglial signalling cascades associated with stroke and Alzheimer's disease

Author

Hooper, Claudie

Subjects
573.851935
Abstract

Microglia, the resident macrophages of the brain, were originally assumed to be passive cells, however increasing evidence suggests that microglia play an active role during development and in neurological disorders. Activated microglia release a variety of toxic inflammatory mediators including reactive nitrogen species, cytokines, glutamate and oxygen free radicals, all of which exert a detrimental effect on neuronal survival if secretion is sustained. Microglial responses depend on the signals received from the surrounding microenvironment. Therefore, in this thesis the effects of albumin, chromogranin A (CgA), ?-amyloid (A?), ischaemia and combined insults (ischaemia plus albumin or ischaemia plus A?) on microglial signalling have been investigated because these activators are associated with the pathology of stroke and/or Alzheimer's disease. Briefly, albumin was found to induce iNOS expression, to cause the release of glutamate and to elicit a calcium-dependent proliferative response in microglia; events that were mediated by a possible interaction with myosin IX. Interestingly, peritoneal macrophages were unresponsive to the same concentrations of albumin. CgA and A? triggered microglial signalling via scavenger receptor-dependent mechanisms. Both activators caused microglia to undergo mitochondrial depolarisation, which precipitated apoptosis. CgA, but not A?, also induced iNOS expression and glutamate release. CgA-induced iNOS expression was mediated by the Src kinase-dependent phosphorylation of ERK. Ischaemia per se did not elicit any discernable effects on microglial signalling. However, microglia subjected to ischaemia followed by albumin treatment endured mitochondrial depolarisation, which led to apoptosis. Similarly, ischaemia followed by A? treatment potentiated the levels of microglial apoptosis and mitochondrial depolarisation induced by A? alone. A common characteristic displayed by microglia subjected to albumin, CgA, A?, or ischaemia was the ability to induce neuronal death. Thus, manipulation of microglial signalling pathways to reduce reactivity and neurotoxicity may provide novel therapeutic strategies for the amelioration of neurodegeneration in disorders such as stroke and Alzheimer's disease.

Published
2004

2. Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.

Author

Killick, R, Ribe, E M, al-Shawi, R, Malik, B., Hooper, Claudie, Fernandes, Clarence, Dobson, R, Nolan, P M, Lourdusamy, A, Furney, S, Lin, K, Breen, G, Wroe, R, To, A W M, Leroy, Karelle, Causevic, Mirsada, Usardi, A, Robinson, M, Noble, Wendy, Williamson, Ritchie, Lunnon, K, Kellie, Stuart, Reynolds, C Hugh, Bazenet, C, Hodges, A, Brion, Jean Pierre, Stephenson, John, Paul Simons, J, Lovestone, S, Killick, R, Ribe, E M, al-Shawi, R, Malik, B., Hooper, Claudie, Fernandes, Clarence, Dobson, R, Nolan, P M, Lourdusamy, A, Furney, S, Lin, K, Breen, G, Wroe, R, To, A W M, Leroy, Karelle, Causevic, Mirsada, Usardi, A, Robinson, M, Noble, Wendy, Williamson, Ritchie, Lunnon, K, Kellie, Stuart, Reynolds, C Hugh, Bazenet, C, Hodges, A, Brion, Jean Pierre, Stephenson, John, Paul Simons, J, and Lovestone, S

Abstract

Although the mechanism of Aβ action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.163., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2012

3. Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice.

Author

Killick, R, Scales, Georgie, Leroy, Karelle, Causevic, Mirsada, Hooper, Claudie, Irvine, Elaine E, Choudhury, Agharul I, Drinkwater, Laura, Kerr, Fiona, Al-Qassab, Hind, Stephenson, John, Yilmaz, Zehra, Giese, K Peter, Brion, Jean Pierre, Withers, Dominic J, Lovestone, S, Killick, R, Scales, Georgie, Leroy, Karelle, Causevic, Mirsada, Hooper, Claudie, Irvine, Elaine E, Choudhury, Agharul I, Drinkwater, Laura, Kerr, Fiona, Al-Qassab, Hind, Stephenson, John, Yilmaz, Zehra, Giese, K Peter, Brion, Jean Pierre, Withers, Dominic J, and Lovestone, S

Abstract

As impaired insulin signalling (IIS) is a risk factor for Alzheimer's disease we crossed mice (Tg2576) over-expressing human amyloid precursor protein (APP), with insulin receptor substrate 2 null (Irs2(-/-)) mice which develop insulin resistance. The resulting Tg2576/Irs2(-/-) animals had increased tau phosphorylation but a paradoxical amelioration of Abeta pathology. An increase of the Abeta binding protein transthyretin suggests that increased clearance of Abeta underlies the reduction in plaques. Increased tau phosphorylation correlated with reduced tau-phosphatase PP2A, despite an inhibition of the tau-kinase glycogen synthase kinase-3. Our findings demonstrate that disruption of IIS in Tg2576 mice has divergent effects on pathological processes-a reduction in aggregated Abeta but an increase in tau phosphorylation. However, as these effects are accompanied by improvement in behavioural deficits, our findings suggest a novel protective effect of disrupting IRS2 signalling in AD which may be a useful therapeutic strategy for this condition., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2009

Catalog

Books, media, physical & digital resources
See catalog results