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1. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis

Author

Hunter Kerry and Hölscher Christian

Subjects
Alzheimer disease, Parkinson's disease, Diabetes, Neuroprotection, Stem cells, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background Type 2 diabetes is a risk factor for Alzheimer's disease (AD), most likely linked to an impairment of insulin signalling in the brain. Therefore, drugs that enhance insulin signalling may have therapeutic potential for AD. Liraglutide (Victoza) and exenatide (Byetta) are novel long-lasting analogues of the GLP-1 incretin hormone and are currently available to treat diabetes. They facilitate insulin signalling via the GLP-1 receptor (GLP-1R). Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation. Therefore, if GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realized. Results In the present study we profiled the GLP-1 receptor agonists liraglutide (Victoza) and lixisenatide (Lyxumia). We measured the kinetics of crossing the blood brain barrier (BBB), activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg bw ip.) when measured 30 min post-injection and at 2.5-25 nmol/kg bw ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. Conclusions Our results suggest that these novel incretin analogues cross the BBB and show physiological activity and neurogenesis in the brain, which may be of use as a treatment of neurodegenerative diseases.

Published
2012
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6. Glucagon like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke:a systematic scoping review

Author

Maskery, M.P., Holscher, C., Jones, S.P., Price, C.I., Strain, W.D., Watkins, C.L., Werring, D.J., Emsley, H.C.A., Maskery, M.P., Holscher, C., Jones, S.P., Price, C.I., Strain, W.D., Watkins, C.L., Werring, D.J., and Emsley, H.C.A.

Abstract

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.

Published
2021

7. Glucagon like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke : a systematic scoping review

Author

Maskery, M.P., Holscher, C., Jones, S.P., Price, C.I., Strain, W.D., Watkins, C.L., Werring, D.J., Emsley, H.C.A., Maskery, M.P., Holscher, C., Jones, S.P., Price, C.I., Strain, W.D., Watkins, C.L., Werring, D.J., and Emsley, H.C.A.

Abstract

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.

Published
2021

11. Selected abstracts

Author

Corkery, P. P., Leek, B. F., Caulfield, B., Garrett, M., Gormley, J. P., OʼDonnell, P. M., Kennedy, N., Sayers, K., Stokes, E., Bresnihan, B., Fitzgerald, O., McGarvey, M. A., Tonra, M., Hooper, A. C. B., Barry, J., Maurer, B., Hussey, J., Gormley, J., Noble, J. G., Alves-Guerreiro, J., Lowe, A. S., Walsh, D. M., NicNiocaill, B., Harte, M., OʼConnor, W. T., OʼHara, A. M., Orren, A., Moran, A. P., Hardiman, D. A., Lee, T. C., Croke, D. T., Tolan, R., McBennett, S., Warmington, S., McGuire, M., Bradford, A., OʼHare, T., MacDermott, M., Lynch, F., OʼRegan, R. G., McLoughlin, P., Quinn, T., Ryan, J. P., Pickering, M., Campion, D. P., Jones, J. F. X., Ryan, S., McNicholas, W. T., Nolan, P., Doyle, F. J., Rackard, S. M., Beddy, P., Campbell, V. A., Bakhle, Y. S., Bell, C., Usher, C., Chan, L., Keenan, A. K., McQuaid, K. E., Cullen, V. C., Smith, E. M., Kelly, A., Lynch, M. A., Freir, D. B., Holscher, C., Herron, C. E., Pearson, H. A., Curran, B. P., OʼConnor, J. J., Quinn, A., McHale, J., Moriarty, D., OʼConnor, J., Glennon, J. C., Van Vliet, B. J., Long, S. K., Kruse, C., Gallagher, H. C., Bacon, C. L., Boland, B., Griffin, A. M., Preisler, J., OʼBrien, L., Regan, C. M., Hurley, S., Kearney, P. J., Slevin, J., Barry-Kinsella, C., Ryan, C. A., Kllleen, O., Glllan, J., Clarke, T., Matthews, T., Corcoran, D., Dunn, E., Geary, M., OʼHerlihy, C., Keane, D., OʼLeary, M. J., Morrison, J. J., Ryan, E., Gorman, W. A., Bourke, A., Larkin, J., Mayes, C., Jenkins, J., Ryan, M., Lalchandani, S., Sheil, O., Lynch, N., Costigan, C., Murphy, J. F., Bhatia, R., Foran, A., Donohue, V., McParland, P., LaSjaunais, P., Rodesch, G., McGinn, M., McAloon, J., OʼLeary, M., Astbury, K., Harmon, D., Sharkey, A., Gaffney, G., OʼRegan, G., McMahon, C., Murray, D., McDermott, C., Woolhead, E., Gillan, J., Cartmill, J. L., Harper, M. A., Al-Shabibi, N., Hanahoe, M., Wingfield, M., Larkin, J. A. M., Bell, A. H., McClure, B. G., Sweeney, L., Martin, D. H., OʼDonoghue, P., Davoren, A., Lucas, G. F., McKiernan, J., Gallagher, D. M. T., Dunne, K. P., Fulena, O., Sheridan, M., Griffin, E., White, M., Deasy, P., OʼRiordan, M., OʼGorman, C., Mongan, C., McCafferkey, M., Henry, G., McKenna, P., OʼMalley, A., Devaney, D., Kelleghan, P., Mooney, E. E., Gillan, J. E., Fitzpatrick, M., McQuillan, K., Heffron, C., Hodnett, P., Curtain, A., OʼConnor, T. C. F., Connell, T. G., Waldron, D., Gorman, W., Bolger, T., OʼKeefe, M., Murphy, J., Dolan, L. M., Traub, A. I., Slattery, M. M., Curley, A. E., Halliday, H. L., Tubman, T. R. J., Kileen, O., Riadha, H., Russell, J., Philips, R., Regan, C., Ali, I., Coughlan, A. C. J., Turner, M. J., Smith, A., OʼFlanagan, D., Igoe, D., Ryan, F., Forde, D., McArdle, E., Ko, D., Bedford, D., Hegarty, M., Dunlevy, B., Corcoran, R., Holohan, T., Feeney, A., McGee, H., Shannon, W., Condon, M., Hyland, C., Sayers, G., Feely, E., Crowley, D., OʼReilly, D., OʼConnell, T., Cronin, M., Johnson, H., Fitzgeraldi, M., Cafferkey, M., Breslin, A., Bonner, C. J., Foley, B., Fitzgerald, M., Wall, P. G., McNamara, E., Costigan, P., Prendergast, T., Foye, K., Cosgrove, C., Keane, A., Murphy, E., OʼDonnell, J., Quinlan, A., Thornton, L., Roch, E. A., Lyons, R. A., Maddocks, A., Barnes, P., Price, L., McCabe, M., Nash, P., Midha, A., Doyle, Y., Kilgallen, A., Wright, P., Ryan, T., De La Harpe, D., Harkins, V., Brennan, C., OʼConnell, V., Evans, D. S., Mhuircheartaigh, Ni J., OʼDonnell, J. M., Rhatigan, A., Shelley, E., Collins, C., Byrne, M., Murphy, A. W., Plunkett, P. K., Murray, A., Bury, G., Lynam, F., McMahon, G., Greally, T., Kane, D., Veale, D., Reece, R., Busteed, S., Bennett, M. W., Stone, M., Molloy, C., OʼConnell, J., Molloy, M. G., Shanahan, F., Guerin, J., Casey, E., Feighery, C., Lin, F., Jackson, J., Pendleton, A., Wright, G. D., Hughes, A. E., OʼGradaigh, D., Debham, I., Compston, J., McEvoy, A., Murphy, E. P., Salonen, D., Payne, P., Lax, M., Lapp, V., Inman, R., OʼRourke, K., Brennan, D., Harty, J., McCarthy, C., OʼByrne, J., Eustace, S., Chirayath, H., Liggett, N. W., Morgan, M. P., Fitzgerald, D. J., McCarthy, C. J., McCarthy, G. M., Lee, R. Z., Wai, K., Nevin, D., Leary, A. O., Lee, R., Casey, E. B., OʼLeary, A., Breen, D., Tuite, D., McInerney, D., Sim, R., Frederic, A. L., Smith, O., White, B., Murphy, M., Silke, C., OʼKeeffe, E., Fanning, N., Spence, L., Parfrey, N. A., McConnell, J. R., Crockard, A. D., Cairns, A. P., Bell, A. L., Kavanagh, O., Moyes, D. A., Finch, M., Rooney, M., Bell, A., Founas, I., El-Magbri, A., Mooney, S., Kennedy, M., Coughlan, R. J., Ramakrishnan, S. A., Gsel, A., Finnerty, O., Burns, M., Yateman, M., Camaco-Hubner, C., Matthews, C. F., Taggart, A., Fuller, K., Murphy, M. S., Phelan, M., Murphy, T. B., Wynne, F., Quane, K., Daly, M., OʼLeary, J., da Silva, I., Bermingham, N., Gogarty, M., Gallagher, L. P., OʼHara, R., Godson, C., Brady, H., Osman, H., El-Rafie, A., Foley-Nolan, D., Kirwan, P., Corcoran, O., Duffy, T., Drummond, F., Madigan, A., Williams, D., Gallagher, P., Hatton, C., Cunningham, S., FitzGerald, O., Minnock, P., Wylie, E., Egan, D., Mc Cormack, J., Shea, M. O., Evans, D., OʼLorcain, P., Comber, H., Evans, A., Jones, J., Garavan, C., Kelleher, K., Boland, M. C., Healy, R., OʼSullivan, M. B., Burke, M., Mc Donald, P., Smithson, R., Glass, J., Mason, C. A., Mullins, N., Nolan, D., McCormick, P., Coughlan, S., Dooley, S., Kelleher, C. C., Hope, A., Murphy, F., Barry, M., Sixsmith, J., MacFarlane, A., MacLeod, C., McElroy, G., OʼLoan, D., Kennedy, F., Kerr, R. M., Lim, J., Allwright, S. P. A., Bradley, F. L., Barry, J. M. G., Long, J., Parry, J. V., Creagh, D., Perry, I. J., Collins, A., Neilson, S., Colwell, N., OʼHalloran, D., OʼNeill, S., McErlain, S., Okasha, M., Gaffney, B., McCarron, P., Hinchion, R., Drew, C., Gavin, A., Fitzpatrick, D., Campbell, R., Wannamethee, S. G., Shaper, A., Friel, S., Kelleher, C., Kee, F., Atterson, C. C., Wilson, E. A., McConnell, J. M., Wheeler, S. M., Watson, J. D., Rahman, Norashikin N., Sheehan, J., Wall, C., Kelleher, B., OʼBroin, S. D., Mullan, R. N., McKeveney, P. J., Hodges, V. M., Winter, P. C., Maxwell, P., Simpson, D. A., Lappin, T. R. J., Maxwell, A. P., Eustace, J. A., Coresh, J., Kutchey, C., Te, P. L., Gimenez, L. F., Scheel, P. J., Walser, M., McMahon, R. A., Clarkson, M., Martin, F., Brady, H. R., Blake, C., OʼMeara, Y. M., Gupta, S., MacKenzie, H., Doyle, S., Fotheringham, T., Haslam, P., Logan, M. P., Conlon, P., Lee, M., Maderna, P., Cottell, D. C., Mitchell, S., Gulmann, C., Østerby, R., Bangstad, H. J., Rljdberg, S., Dempsey, M., Nathwani, S., Ryan, M. P., McMahon, B., Stenson, C., Murtagh, H., Brown, J. H., Doran, P., McGinty, A., Little, M. A., OʼBrien, E., Owens, P., Holian, J., Mee, F., Walshe, J. J., Omer, S. A., Power, D., Diamond, P., Watson, R. W., Shahsafei, A., Jiang, T., Brenner, B. M., Mackenzie, H. S., Neary, J., Dorman, A., Keoghan, M., Campbell, E., Walshe, J., Little, M., Nee, L., OʼCeallaigh, C., McGlynn, H., Bergin, E., Keane, T., Gormley, G., Watson, A., Atta, M. G., Perl, T. M., Song, X., Healy, E., Leonard, M., Lynch, J., Watson, A. J., Lappin, D., Lappin, D. W. P., Hannan, K., Burne, M., Daniels, F., Rabb, H., McBride, B., Kieran, N., Shortt, C., Codd, M., Murray, F., McCormack, A., Brown, C., Wong, C., Dorman, A. M., Keogan, M., Donohue, J., Farrell, J., Donohoe, J., OʼBroin, S., Balfe, A., Mellotte, G. J., Abraham, K. A., McGorrian, C., Wood, A. E., Neligan, M., Kelly, B. D., Finnegan, P., Cormican, M., Callaghan, J., Crean, J. K. G., Moffitt, T. A., Devlin, H. L., Garrett, P. J., Soosay, A., OʼNeill, D., Counihan, A., Hickey, D., Keogan, M. T., Harvey, K., OʼRiordan, E., Waldek, S., Kalra, P. A., OʼDonoghue, D. J., Foley, R. N., Kelliher, D., Mellotte, G., Giblin, L., Keogh, J. A. B., OʼConnell, M., OʼMeara, A., Breatnach, F., Gillick, J., Tazawa, H., Puri, P., Molloy, E., OʼNeill, A. J., Sheridan-Pereira, M., Fitzpatrick, J. M., Webb, D. W., Watson, R. W. G., Linnane, B., OʼDonnell, C., Clarke, T. A., Martin, C., McKay, M., McBrien, J., Glynn, F., OʼDonovan, C., Hall, W. W., Smith, J., Khair, K., Liesner, R., Hann, I. M., Smith, O. P., Gallagher, S., Mahony, M. J., Hilal, A., Cosgrove, J. F., Monaghan, C., Craig, B., Walsh, K., Duff, D., Slizlok, P. O., Halahakoon, C., McMillan, S., Dalzell, E. E., McCaughan, J., Redmond, A. O. B., DeCaluwe, D., Yoneda, A., Akl, U., Dempsey, E., Farrell, M., Webb, D., Elabbas, A., Fox, G., Gormally, S., Grant, B., Corkey, C. W. B., Nicholson, A., Murphy, A., OʼGrady, P., Barry, O., Stewart, M. C., Alderdice, F., Matthews, T. G., McDonnell, M., McGarvey, C., OʼRegan, M., Chróinín, Ní M., Tormey, P., Ennis, S., Green, A. J., Abbas, S., OʼMarcaigh, A., Conran, M., Crushell, E., Saidi, A., Curran, P., Donoghue, V., King, M. D., Elnazir, B., Leonard, J., Kavanagh, C., Brown, D., Corrigan, N., McCord, B., Quinn, M., OʼConnell, L., Mcdonagh, B., Awan, A., Gill, D., Kakkar, R., Warner, J. A., OʼConnor, C., Herzig, M., Twomey, A., White, M. J., Sweeney, B., Surana, R., Hodgson, A., Rafferty, M., Livingstone, W., Peake, D., Wassemer, E., Whitehouse, W., Abdullah, N., Al-Hassan, A., Oslizlok, P., OʼConnell, N., Balding, J., Livingstone, W. J., Healy, M., Mynett-Johnson, L., McAllister, I., Dick, A. C., Herron, B., Boston, V. E., Callaghan, C. O., Brien, D. O., Walsh, A., Philip, M., McShane, D., Hoey, M. C. V., Sharif, F., McDermott, M., Dillon, M., Drumm, B., Rowland, M., Imrie, C., Kelleher, S., Bourke, B., Iqbal, M., Ziedan, Y., OʼNeill, M., OʼRiordan, S., Basheer, S. M. B., OʼCallaghan, S., Chong, A., Kelly, M., Nicholson, A. J., Cooke, R., Sreenan, C., Fallon, M., Denham, B., Dowding, V., Cussen, G., McManus, V., Hensey, O., Monaghan, H., Basheer, S. N., Quinn, E., Hoey, H. M. C. V., Mohamed, S., Ramesh, R. R., Mayne, P., Tracy, E., Gormally, S. M., Curtis, E., McCallion, N., Watson, R., OʼMahony, O., Keegan, M., Ward, K., Barton, D., Poulton, J., Treacy, E., Honour, J., deCaluwe, D., Chróinín, Ni M., Cosgrove, J., Chaudhry, T. S., Long, N. M., Lynch, B., Lasjaunais, P., McDonald, D. G. M., McMenamin, J. B., Farrell, M. J., Roche, E. F., Menon, A., Buckley, C., Mackey, A., Ohlandieck, K., Das, A., Reilly, D., Killeen, O., Harper, J., Roche, E., Hoey, H., Caird, J., OʼBrien, D., Allcutt, D., Farrington, N., Murphy, J. F. A., Savage, J. M., Sands, A. J., Casey, F. A., Craig, B. G., Dornan, J. C., Johnston, J., Patterson, C., Lynch, C., Mulholland, H. C., Watkins, D. C., Young, I., Cran, G., Boreham, C. A. G., McCallion, W. A., Clements, N. F., Stevenson, M. R., Macpherson, C., Jenkins, L., Thompson, A. J., Shields, M. D., Taylor, R. T., Kerr, R., Hughes, J. L., Stewart, M., Jackson, P., Fitzpatrick, C., Rasheed, M., Colhoun, E., Bailie, A. G., Gray, S., Brown, S., Curley, A., Sweet, D. G., MacMahon, K. J., OʼConnor, C. M., Nichelson, A., Lynch, N. E., Finch, D., Foley, M., Scallan, E., Dillon, B., Lyons, S., OʼLoughlin, R., Ward, M., Nally, R., Harkin, A., Kelly, J. P., Leonard, B. E., Magee, P., Connor, T. J., Shen, Y., McCullough, G. R., McDonough, S. M., Niocaill, Nic B., Cramp, A. F. L., Hynes, M., Corkery, P., Carey, M., McGarrigle, D., Higgins, S., Murray, H., Moran, C. J., Dennedy, M. C., Brosnan, J., Morris, L., Sheppard, B. L., Black, A., Wilkins, B., Folan-Curran, J., Skelton, K., Owens, M., Nemeroff, C., Houlihan, D., OʼKeeffe, C., Nolan, N., McCormick, P. A., Baird, A. W., Raducan, I., Corcoran, P., Brennan, R., Molloy, P., Friel, A., Maher, M., Glennon, M., Smith, T., Nolan, A., Houghton, J. A., Carroll, O., Colleran, S., OʼCuinn, G., Snow, H. M., OʼRegan, D., Markos, H. F., Pollock, K., Cannon, D. M., McBean, G., OʼRiordan, A., Quinlan, L. R., Kane, M. T., Higglns, B. D., Moriarty, D. M., Fitzgerald, D., Katkada, A., Canny, G., MacMathuna, P., OʼDonoghue, D., OʼDonovan, M. M., Schuur, A. G., Murphy, K. J., Foley, A. G., ten Bruggencate, S. J. M., and Ireland, L.

Published
2000
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12. MCU knockdown in hippocampal neurons improves memory performance of an Alzheimer’s disease mouse model

Author

Cai Hongyan, Qiao Jing, Chen Siru, Yang Junting, Hölscher Christian, Wang Zhaojun, Qi Jinshun, and Wu Meina

Subjects
Alzheimer’s disease, mitochondrial calcium uniporter, memory behavior deficit, neuroinflammation response, mitophagy, Biochemistry, QD415-436, Genetics, QH426-470
Abstract

Alzheimer’s disease (AD) is a progressive and degenerative disorder accompanied by cognitive decline, which could be promoted by mitochondrial dysfunction induced by mitochondrial Ca 2+ (mCa 2+) homeostasis Mitochondrial calcium uniporter (MCU), a key channel of mCa 2+ uptake, may be a target for AD treatment. In the present study, we reveal for the first time that MCU knockdown in hippocampal neurons improves the memory performance of APP/PS1/tau mice through radial arm maze task. Western blot analysis, transmission electron microscopy (TEM), Golgi staining, immunohistochemistry (IHC) and ELISA results demonstrate that MCU knockdown in hippocampal neurons upregulates the levels of postsynaptic density protein 95 (PSD95) and synaptophysin (SYP), and increases the numbers of synapses and dendritic spines. Meanwhile, MCU knockdown in hippocampal neurons decreases the neuroinflammatory response induced by astrogliosis and high levels of IL-1β and TNF-α, and improves the PINK1-Parkin mitophagy signaling pathway and increases the level of Beclin-1 but decreases the level of P62. In addition, MCU knockdown in hippocampal neurons recovers the average volume and number of mitochondria. These data confirm that MCU knockdown in hippocampal neurons improves the memory performance of APP/PS1/tau mice through ameliorating the synapse structure and function, relieving the inflammation response and recovering mitophagy, indicating that MCU inhibition has the potential to be developed as a novel therapy for AD.

Published
2022
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13. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology

Author

Olmos-Alonso A, St, Schetters, Sri S, Askew K, Mancuso R, Vargas-Caballero M, Holscher C, Vh, Perry, and Diego Gomez-Nicola

Subjects
Human medicine
Abstract

Microglial proliferation and activation is a hallmark of Alzheimer's disease. Olmos-Alonso et al. show that microglial proliferation in Alzheimer's disease tissue correlates with overactivation of the colony-stimulating factor 1 receptor (CSF1R) pathway. CSF1R blockade arrests microglial proliferation and activation in a mouse model of Alzheimer-like pathology and slows disease progression.Microglial proliferation and activation is a hallmark of Alzheimer's disease. Olmos-Alonso et al. show that microglial proliferation in Alzheimer's disease tissue correlates with overactivation of the colony-stimulating factor 1 receptor (CSF1R) pathway. CSF1R blockade arrests microglial proliferation and activation in a mouse model of Alzheimer-like pathology and slows disease progression.The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-beta plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-beta plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease.

Published
2016

14. Two-wavelength electronic speckle-pattern interferometry for the analysis ofdiscontinuous deformation fields

Author

Gulker, G., Haack, O., Hinsch, K.D., Holscher, C., Kuls, J., and Platen, W.

Subjects
Holographic interferometry -- Methods, Diffraction patterns -- Analysis, Deformations (Mechanics) -- Analysis, Astronomy, Physics
Abstract

Ambiguity in the conversion of phase measurements to deformation values restricts the applicability of electronic speckle-pattern interferometry. The use of two wavelengths greatly relaxes this restriction.

Published
1992

15. Simultaneous online tracking of adjacent and non-adjacent dependencies in statistical learning

Author

Vuong, L.C., Meyer, A.S., Christiansen, M.H., Carlson, L., Holscher, C., Shipley, T., Carlson, L., Holscher, C., and Shipley, T.

Subjects
Psycholinguistics, Language and Communication [DI-BCB_DCC_Theme 1], Social and Behavioral Sciences
Abstract

Item does not contain fulltext When children learn their native language, they have to deal with a confusing array of dependencies between various elements in an utterance. Some of these dependencies may be adjacent to one another whereas others can be separated by considerable intervening material. Research on statistical learning has begun to explore how such adjacent and nonadjacent dependencies may be learned—but in separate studies. In this paper, we investigate whether both types of dependencies can be learned together, similarly to the task facing young children. Statistical learning of adjacent and non-adjacent dependencies was assessed using a modified serial-reaction-time task. The results showed (i) increasing online sensitivity to both dependency types during training, and (ii) non-adjacent dependency learning being highly correlated with adjacent dependency learning. These results suggest that adjacency and non-adjacency learning can occur in parallel and that they might be subserved by a common statistical learning mechanism.

Published
2011

18. Simultaneous Online Tracking of Adjacent and Non-Adjacent Dependencies in Statistical Learning

Author

Carlson, L., Holscher, C., Shipley, T., Vuong, L.C., Meyer, A.S., Christiansen, M.H., Carlson, L., Holscher, C., Shipley, T., Vuong, L.C., Meyer, A.S., and Christiansen, M.H.

Abstract

Item does not contain fulltext, When children learn their native language, they have to deal with a confusing array of dependencies between various elements in an utterance. Some of these dependencies may be adjacent to one another whereas others can be separated by considerable intervening material. Research on statistical learning has begun to explore how such adjacent and nonadjacent dependencies may be learned—but in separate studies. In this paper, we investigate whether both types of dependencies can be learned together, similarly to the task facing young children. Statistical learning of adjacent and non-adjacent dependencies was assessed using a modified serial-reaction-time task. The results showed (i) increasing online sensitivity to both dependency types during training, and (ii) non-adjacent dependency learning being highly correlated with adjacent dependency learning. These results suggest that adjacency and non-adjacency learning can occur in parallel and that they might be subserved by a common statistical learning mechanism.

Published
2011

26. Selected abstracts

Author

Corkery, P. P., Leek, B. F., Caulfield, B., Garrett, M., Gormley, J. P., O’Donnell, P. M., Kennedy, N., Sayers, K., Stokes, E., Bresnihan, B., Fitzgerald, O., McGarvey, M. A., Tonra, M., Hooper, A. C. B., Barry, J., Maurer, B., Hussey, J., Gormley, J., Noble, J. G., Alves-Guerreiro, J., Lowe, A. S., Walsh, D. M., NicNiocaill, B., Harte, M., O’Connor, W. T., O’Hara, A. M., Orren, A., Moran, A. P., Hardiman, D. A., Lee, T. C., Croke, D. T., Tolan, R., McBennett, S., Warmington, S., McGuire, M., Bradford, A., O’Hare, T., MacDermott, M., Lynch, F., O’Regan, R. G., McLoughlin, P., Quinn, T., Ryan, J. P., Pickering, M., Campion, D. P., Jones, J. F. X., Ryan, S., McNicholas, W. T., Nolan, P., Doyle, F. J., Rackard, S. M., Beddy, P., Campbell, V. A., Bakhle, Y. S., Bell, C., Usher, C., Chan, L., Keenan, A. K., McQuaid, K. E., Cullen, V. C., Smith, E. M., Kelly, A., Lynch, M. A., Freir, D. B., Holscher, C., Herron, C. E., Pearson, H. A., Curran, B. P., O’Connor, J. J., Quinn, A., McHale, J., Moriarty, D., O’Connor, J., Glennon, J. C., Van Vliet, B. J., Long, S. K., Kruse, C., Gallagher, H. C., Bacon, C. L., Boland, B., Griffin, A. M., Preisler, J., O’Brien, L., Regan, C. M., Hurley, S., Kearney, P. J., Slevin, J., Barry-Kinsella, C., Ryan, C. A., Kllleen, O., Glllan, J., Clarke, T., Matthews, T., Corcoran, D., Dunn, E., Geary, M., O’Herlihy, C., Keane, D., Slattery, M. M., O’Leary, M. J., Morrison, J. J., Ryan, E., Gorman, W. A., Bourke, A., Larkin, J., Mayes, C., Jenkins, J., Ryan, M., Lalchandani, S., Sheil, O., Lynch, N., Costigan, C., Murphy, J. F., Bhatia, R., Foran, A., Donohue, V., McParland, P., LaSjaunais, P., Rodesch, G., McGinn, M., McAloon, J., O’Leary, M., Astbury, K., Harmon, D., Sharkey, A., Gaffney, G., O’Regan, G., McMahon, C., Murray, D., McDermott, C., Woolhead, E., Gillan, J., Cartmill, J. L., Harper, M. A., Al-Shabibi, N., Hanahoe, M., Wingfield, M., Larkin, J. A. M., Bell, A. H., McClure, B. G., Sweeney, L., Martin, D. H., O’Donoghue, P., Davoren, A., Lucas, G. F., McKiernan, J., Gallagher, D. M. T., Dunne, K. P., Fulena, O., Sheridan, M., Griffin, E., White, M., Deasy, P., O’Riordan, M., O’Gorman, C., Mongan, C., McCafferkey, M., Henry, G., McKenna, P., O’Malley, A., Devaney, D., Kelleghan, P., Mooney, E. E., Gillan, J. E., Fitzpatrick, M., McQuillan, K., Heffron, C., Hodnett, P., Curtain, A., O’Connor, T. C. F., Connell, T. G., Waldron, D., Gorman, W., Bolger, T., O’Keefe, M., Murphy, J., Dolan, L. M., Traub, A. I., Slattery, M. M., O’Leary, M. J., Curley, A. E., Halliday, H. L., Tubman, T. R. J., Kileen, O., Riadha, H., Russell, J., Philips, R., Regan, C., Ali, I., Coughlan, A. C. J., Turner, M. J., Smith, A., O’Flanagan, D., Igoe, D., Ryan, F., Forde, D., McArdle, E., Ko, D., Bedford, D., Hegarty, M., Dunlevy, B., Corcoran, R., Holohan, T., Feeney, A., McGee, H., Shannon, W., Condon, M., Hyland, C., Sayers, G., Feely, E., Crowley, D., O’Reilly, D., O’Connell, T., Cronin, M., Johnson, H., Fitzgeraldi, M., Cafferkey, M., Breslin, A., Bonner, C. J., Foley, B., Fitzgerald, M., Wall, P. G., McNamara, E., Costigan, P., Prendergast, T., Foye, K., Cosgrove, C., Keane, A., Murphy, E., O’Donnell, J., Quinlan, A., Thornton, L., Roch, E. A., Lyons, R. A., Maddocks, A., Barnes, P., Price, L., McCabe, M., Nash, P., Midha, A., Doyle, Y., Kilgallen, A., Wright, P., Ryan, T., De La Harpe, D., Harkins, V., Brennan, C., O’Connell, V., Evans, D. S., Ni Mhuircheartaigh, J., O’Donnell, J. M., Rhatigan, A., Shelley, E., Collins, C., Byrne, M., Murphy, A. W., Plunkett, P. K., Murray, A., Bury, G., Lynam, F., McMahon, G., Greally, T., Kane, D., Veale, D., Reece, R., Busteed, S., Bennett, M. W., Stone, M., Molloy, C., O’Connell, J., Molloy, M. G., Shanahan, F., Guerin, J., Casey, E., Feighery, C., Lin, F., Jackson, J., Pendleton, A., Wright, G. D., Hughes, A. E., O’Gradaigh, D., Debham, I., Compston, J., McEvoy, A., Murphy, E. P., Salonen, D., Payne, P., Lax, M., Lapp, V., Inman, R., O’Rourke, K., Brennan, D., Harty, J., McCarthy, C., O’Byrne, J., Eustace, S., Chirayath, H., Liggett, N. W., Morgan, M. P., Fitzgerald, D. J., McCarthy, C. J., McCarthy, G. M., Lee, R. Z., Wai, K., Nevin, D., Leary, A. O., Lee, R., Leary, A. O., Casey, E. B., Leary, A. O., O’Leary, A., Breen, D., Tuite, D., McInerney, D., Sim, R., Frederic, A. L., Smith, O., White, B., Murphy, M., Silke, C., O’Keeffe, E., Fanning, N., Spence, L., Parfrey, N. A., McConnell, J. R., Crockard, A. D., Cairns, A. P., Bell, A. L., Kavanagh, O., Moyes, D. A., Finch, M., Rooney, M., Bell, A., Founas, I., El-Magbri, A., Mooney, S., Kennedy, M., Coughlan, R. J., Ramakrishnan, S. A., Gsel, A., Finnerty, O., Burns, M., Yateman, M., Camaco-Hubner, C., Matthews, C. F., Taggart, A., Fuller, K., Murphy, M. S., Phelan, M., Murphy, T. B., Wynne, F., Quane, K., Daly, M., O’Leary, J., da Silva, I., Bermingham, N., Gogarty, M., Gallagher, L. P., O’Hara, R., Godson, C., Brady, H., Osman, H., El-Rafie, A., Foley-Nolan, D., Kirwan, P., Corcoran, O., Duffy, T., Drummond, F., Madigan, A., Williams, D., Gallagher, P., Hatton, C., Cunningham, S., FitzGerald, O., Minnock, P., Wylie, E., Egan, D., Mc Cormack, J., Shea, M. O., Evans, D., O’Lorcain, P., Comber, H., Evans, A., Jones, J., Garavan, C., Kelleher, K., Boland, M. C., Healy, R., O’Sullivan, M. B., Burke, M., Mc Donald, P., Smithson, R., Glass, J., Mason, C. A., Mullins, N., Nolan, D., McCormick, P., Coughlan, S., Dooley, S., Kelleher, C. C., Hope, A., Murphy, F., Barry, M., Sixsmith, J., MacFarlane, A., MacLeod, C., McElroy, G., O’Loan, D., Kennedy, F., Kerr, R. M., Lim, J., Allwright, S. P. A., Bradley, F. L., Barry, J. M. G., Long, J., Parry, J. V., Creagh, D., Perry, I. J., Collins, A., Neilson, S., Colwell, N., O’Halloran, D., O’Neill, S., McErlain, S., Okasha, M., Gaffney, B., McCarron, P., Hinchion, R., Drew, C., Gavin, A., Fitzpatrick, D., Campbell, R., Wannamethee, S. G., Shaper, A., Friel, S., Kelleher, C., Kee, F., Atterson, C. C., Wilson, E. A., McConnell, J. M., Wheeler, S. M., Watson, J. D., Norashikin Rahman, N., Sheehan, J., Wall, C., Kelleher, B., O’Broin, S. D., Mullan, R. N., McKeveney, P. J., Hodges, V. M., Winter, P. C., Maxwell, P., Simpson, D. A., Lappin, T. R. J., Maxwell, A. P., Eustace, J. A., Coresh, J., Kutchey, C., Te, P. L., Gimenez, L. F., Scheel, P. J., Walser, M., McMahon, R. A., Clarkson, M., Martin, F., Brady, H. R., Blake, C., O’Meara, Y. M., Gupta, S., MacKenzie, H., Doyle, S., Fotheringham, T., Haslam, P., Logan, M. P., Conlon, P., Lee, M., Maderna, P., Cottell, D. C., Mitchell, S., Gulmann, C., Østerby, R., Bangstad, H. J., Rljdberg, S., Dempsey, M., Nathwani, S., Ryan, M. P., McMahon, B., Stenson, C., Murtagh, H., Brown, J. H., Doran, P., McGinty, A., Little, M. A., O’Brien, E., Owens, P., Holian, J., Mee, F., Walshe, J. J., Omer, S. A., Power, D., Diamond, P., Watson, R. W., Shahsafei, A., Jiang, T., Brenner, B. M., Mackenzie, H. S., Neary, J., Dorman, A., Keoghan, M., Campbell, E., Walshe, J., Little, M., Nee, L., O’Ceallaigh, C., McGlynn, H., Bergin, E., Garrett, P. J., Keane, T., Gormley, G., Watson, A., Atta, M. G., Perl, T. M., Song, X., Healy, E., Leonard, M., Lynch, J., Watson, A. J., Lappin, D., Lappin, D. W. P., Hannan, K., Burne, M., Daniels, F., Rabb, H., McBride, B., Kieran, N., Shortt, C., Codd, M., Murray, F., McCormack, A., Brown, C., Wong, C., Dorman, A. M., Keogan, M., Donohue, J., Farrell, J., Donohoe, J., O’Broin, S., Balfe, A., Mellotte, G. J., Abraham, K. A., McGorrian, C., Wood, A. E., Neligan, M., Kelly, B. D., Finnegan, P., Cormican, M., Callaghan, J., Crean, J. K. G., Moffitt, T. A., Devlin, H. L., Garrett, P. J., Soosay, A., O’Neill, D., Counihan, A., Hickey, D., Keogan, M. T., Harvey, K., O’Riordan, E., Waldek, S., Kalra, P. A., O’Donoghue, D. J., Foley, R. N., O’Riordan, A., Kelliher, D., Mellotte, G., Giblin, L., Keogh, J. A. B., O’Connell, M., O’Meara, A., Breatnach, F., Gillick, J., Tazawa, H., Puri, P., Molloy, E., O’Neill, A. J., Sheridan-Pereira, M., Fitzpatrick, J. M., Webb, D. W., Watson, R. W. G., Linnane, B., O’Donnell, C., Clarke, T. A., Martin, C., McKay, M., McBrien, J., Glynn, F., O’Donovan, C., Hall, W. W., Smith, J., Khair, K., Liesner, R., Hann, I. M., Smith, O. P., Gallagher, S., Mahony, M. J., Hilal, A., Cosgrove, J. F., Monaghan, C., Craig, B., Al-Hassan, A., Walsh, K., Duff, D., Slizlok, P. O., Halahakoon, C., MacPherson, C., McMillan, S., Dalzell, E. E., McCaughan, J., Redmond, A. O. B., DeCaluwe, D., Yoneda, A., Akl, U., Dempsey, E., Farrell, M., Webb, D., Elabbas, A., Fox, G., Gormally, S., Grant, B., Corkey, C. W. B., Nicholson, A., Murphy, A., O’Grady, P., Barry, O., Macpherson, C., Stewart, M. C., Alderdice, F., Matthews, T. G., McDonnell, M., McGarvey, C., O’Regan, M., Ní Chróinín, M., Tormey, P., Ennis, S., Green, A. J., Abbas, S., O’Marcaigh, A., Conran, M., Crushell, E., Saidi, A., Curran, P., Donoghue, V., King, M. D., Elnazir, B., Leonard, J., Kavanagh, C., Brown, D., Corrigan, N., McCord, B., Quinn, M., O’Connell, L., Mcdonagh, B., Awan, A., Gill, D., Kakkar, R., Sweet, D. G., Warner, J. A., O’Connor, C., Herzig, M., Twomey, A., White, M. J., Sweeney, B., Surana, R., Hodgson, A., Rafferty, M., Livingstone, W., Peake, D., Wassemer, E., Whitehouse, W., Abdullah, N., Al-Hassan, A., Oslizlok, P., O’Connell, N., Balding, J., Livingstone, W. J., Healy, M., Mynett-Johnson, L., McAllister, I., Dick, A. C., Herron, B., Boston, V. E., Callaghan, C. O., Brien, D. O., Walsh, A., Philip, M., McShane, D., Hoey, M. C. V., Sharif, F., McDermott, M., Dillon, M., Drumm, B., Rowland, M., Imrie, C., Kelleher, S., Bourke, B., Iqbal, M., Ziedan, Y., O’Neill, M., O’Riordan, S., Basheer, S. M. B., O’Callaghan, S., Chong, A., Kelly, M., Nicholson, A. J., Cooke, R., Sreenan, C., Fallon, M., Denham, B., Dowding, V., Cussen, G., McManus, V., Hensey, O., Monaghan, H., Basheer, S. N., Quinn, E., Hoey, H. M. C. V., Mohamed, S., Ramesh, R. R., Mayne, P., Tracy, E., Gormally, S. M., Curtis, E., McCallion, N., Watson, R., O’Mahony, O., Keegan, M., Ward, K., Barton, D., Poulton, J., Treacy, E., Honour, J., deCaluwe, D., Ni Chróinín, M., Cosgrove, J., Chaudhry, T. S., Long, N. M., Lynch, B., Lasjaunais, P., McDonald, D. G. M., McMenamin, J. B., Farrell, M. J., Roche, E. F., Menon, A., Buckley, C., Mackey, A., Ohlandieck, K., Das, A., Reilly, D., Killeen, O., Harper, J., Roche, E., Hoey, H., Caird, J., O’Brien, D., Allcutt, D., Farrington, N., Murphy, J. F. A., Savage, J. M., Sands, A. J., Casey, F. A., Craig, B. G., Dornan, J. C., Johnston, J., Patterson, C., Lynch, C., Mulholland, H. C., Watkins, D. C., Young, I., Cran, G., Boreham, C. A. G., McCallion, W. A., Clements, N. F., Stevenson, M. R., Macpherson, C., O’Donoghue, D., Jenkins, L., Thompson, A. J., Shields, M. D., Taylor, R. T., Kerr, R., Hughes, J. L., Stewart, M., Jackson, P., Fitzpatrick, C., Rasheed, M., Colhoun, E., Bailie, A. G., Gray, S., Brown, S., Curley, A., Sweet, D. G., MacMahon, K. J., O’Connor, C. M., Nichelson, A., Lynch, N. E., Finch, D., Foley, M., Scallan, E., Dillon, B., Lyons, S., O’Loughlin, R., Ward, M., Nally, R., Harkin, A., Kelly, J. P., Leonard, B. E., Nic Niocaill, B., Magee, P., Connor, T. J., Shen, Y., McCullough, G. R., McDonough, S. M., Nic Niocaill, B., Cramp, A. F. L., Hynes, M., Corkery, P., Carey, M., McGarrigle, D., Higgins, S., Murray, H., Moran, C. J., Dennedy, M. C., Brosnan, J., Morris, L., Sheppard, B. L., Black, A., Wilkins, B., Folan-Curran, J., Skelton, K., Owens, M., Nemeroff, C., Houlihan, D., O’Keeffe, C., Nolan, N., McCormick, P. A., Baird, A. W., Raducan, I., Corcoran, P., Brennan, R., Molloy, P., Friel, A., Maher, M., Glennon, M., Smith, T., Nolan, A., Houghton, J. A., Carroll, O., Colleran, S., O’Cuinn, G., Snow, H. M., O’Regan, D., Markos, H. F., Pollock, K., Cannon, D. M., McBean, G., O’Riordan, A., Quinlan, L. R., Kane, M. T., Higglns, B. D., Moriarty, D. M., Fitzgerald, D., Katkada, A., Canny, G., MacMathuna, P., O’Donoghue, D., O’Donovan, M. M., Schuur, A. G., Murphy, K. J., Foley, A. G., ten Bruggencate, S. J. M., and Ireland, L.

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33. Interleukin-4 receptor alpha-deficient BALB/c mice show an unimpaired T helper 2 polarization in response to Leishmania major infection.

Author

Mohrs, M, Holscher, C, and Brombacher, F

Abstract

We recently generated interleukin-4 (IL-4) receptor alpha-deficient (IL-4Ralpha(-/-)) BALB/c mice and showed evidence for a protective role of IL-13-mediated functions in leishmaniasis. In this study, we investigated the IL-4 expression and T helper 2 (Th2) development in Leishmania major-infected IL-4Ralpha(-/-) mice. Here we show that the early burst of IL-4 expression observed in L. major-infected BALB/c mice is independent of IL-4Ralpha-mediated functions. Subsequently, we confirmed an impaired Th2 development in vitro. Unexpectedly, during L. major infection, isolated CD4(+) IL-4Ralpha(-/-) T cells expressed high IL-4- but low gamma interferon (IFN-gamma)-specific mRNA, comparable to Th2-polarized BALB/c CD4(+) cells and in contrast to Th1-polarized C57BL/6 CD4(+) cells. Since antigen-specific restimulated popliteal lymph node cells (PLN) of IL-4Ralpha(-/-) mice also responded with high IL-4 but low IFN-gamma production, comparable to Th2-polarized cells from wild-type BALB/c mice and in contrast to Th1-polarized C57BL/6 cells, these results suggested an unimpaired Th2 polarization during an established infection with L. major. To further define the observed IL-4 receptor-independent Th2 cell phenotype, we determined an independent Th2 marker, the IL-12 receptor beta-2 (IL-12Rbeta2)-specific transcript levels of CD4(+) T cells. Confirming Th2 polarization in L. major-infected IL-4Ralpha(-/-) mice, comparable IL-12Rbeta2 message levels between CD4(+) T cells from infected IL-4Ralpha(-/-) mice and Th2 cells from BALB/c mice were found, whereas Th1-polarized C57BL/6 cells showed strikingly increased IL-12Rbeta2 expression levels. These results indicate that signals mediated by the IL-4Ralpha are not necessary to induce and sustain an efficient IL-4 expression and Th2 polarization in L. major-infected BALB/c mice and suggest that IL-4Ralpha-independent mechanisms underlie the default Th2 development in L. major-infected BALB/c mice.

Published
2000

36. Prostaglandins play a role in memory consolidation in the chick

Author

Holscher, C.

Abstract

Previous studies showed that inhibitors of cyclooxygenases have amnesic effects in chicks in a passive avoidance task. The onset of amnesia has a delay of 2 h post-training. To investigate if this effect is due to the inhibition of induction of the enzyme during learning, the release of cyclooxygenase products into the extracellular fluid was measured at 1, 2 and 3 h post-training. A cyclooxygenase inhibitor, ibuprofen, inhibited the training-dependent increase of cyclooxygenase products only 2 h and 3 h after learning when injected pre-training, as did dexamethasone which prevents cyclooxygenase induction, and SC58125 (1,2-diarylcyclopentene), an inhibitor of inducible cyclooxygenase. Injections 30 min post-training showed the same effect with the exception of dexamethasone. Injecting SC58125, ibuprofen, indomethacin, or dexamethasone i.c. before training showed amnesic effects for training on a one-trial passive avoidance task at 2 h but not 1 h after training. Injections 30 min post-training produced the same effects with the exception of dexamethasone. I conclude that cyclooxygenases are induced during training and that cyclooxygenase products are of importance in memory formation of the chick.

Published
1995
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37. Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17

Author

Schulz, S. M., Köhler, G., Schütze, N., Knauer, J., Reinhard Straubinger, Chackerian, A. A., Witte, E., Wolk, K., Sabat, R., Iwakura, Y., Holscher, C., Müller, U., Kastelein, R. A., Alber, G., and Publica

Subjects
Salmonella enterica
Abstract

IL-12 is essential for protective T cell-mediated immunity against Salmonella infection. To characterize the role of the related cytokine IL-23, wild-type (WT) C57BL/6 and p19 -/-mice were infected systemically with an attenuated strain of Salmonella enterica serovar Enteritidis (S. Enteritidis). IL-23-deficient mice controlled infection with S. Enteritidis similarly as WT mice. Similar IFN-{gamma} production as compared with WT mice, but defective IL-17A and IL-22 production was found in the absence of IL-23. Nevertheless, although IL-23 is required for T cell-dependent cytokine responses, IL-23 is dispensable for protection against S. Enteritidis when IL-12 is present. To analyze the role of IL-23 in the absence of IL-12, low doses of S. Enteritidis were administered to p35 -/- mice (lacking IL-12), p35/19 -/- mice (lacking IL-12 and IL-23), p35/40 -/- mice (lacking IL-12, IL-23, and homodimeric IL-12p40), or p35/IL-17A -/- mice (lacking IL-12 and IL-17A). We found survival of p35 -/-and p35/IL-17A -/- mice, whereas p35/19 -/- and p35/40 -/-mice died within 3-6 wk and developed liver necrosis. This indicates that IL-23, but not homodimeric IL-12p40, is required for protection, which, surprisingly, is independent of IL-17A. Moreover, protection was associated with IL-22, but not IL-17F or IL-21 expression or with neutrophil recruitment. Finally, anti-IL-22 treatment of S. Enteritidis-infected p35 -/- mice resulted in liver necrosis, indicating a central role of IL-22 in hepatocyte protection during salmonellosis. In conclusion, IL-23-dependent IL-22, but not IL-17 production is associated with protection against systemic infection with S. Enteritidis in the absence of IL-12.

38. Entropy and a sub-group of geometric measures of paths predict the navigability of an environment

Author

Yesiltepe, D., Fernández Velasco, P., Coutrot, A., Ozbil Torun, A., Wiener, Jan M., Holscher, C., Hornberger, M., Conroy Dalton, R., Spiers, H. J., Yesiltepe, D., Fernández Velasco, P., Coutrot, A., Ozbil Torun, A., Wiener, Jan M., Holscher, C., Hornberger, M., Conroy Dalton, R., and Spiers, H. J.

Abstract

Despite extensive research on navigation, it remains unclear which features of an environment predict how difficult it will be to navigate. We analysed 478,170 trajectories from 10,626 participants who navigated 45 virtual environments in the research app-based game Sea Hero Quest. Virtual environments were designed to vary in a range of properties such as their layout, number of goals, visibility (varying fog) and map condition. We calculated 58 spatial measures grouped into four families: task-specific metrics, space syntax configurational metrics, space syntax geometric metrics, and general geometric metrics. We used Lasso, a variable selection method, to select the most predictive measures of navigation difficulty. Geometric features such as entropy, area of navigable space, number of rings and closeness centrality of path networks were among the most significant factors determining the navigational difficulty. By contrast a range of other measures did not predict difficulty, including measures of intelligibility. Unsurprisingly, other task-specific features (e.g. number of destinations) and fog also predicted navigation difficulty. These findings have implications for the study of spatial behaviour in ecological settings, as well as predicting human movements in different settings, such as complex buildings and transport networks and may aid the design of more navigable environments.

39. No link between handedness and spatial navigation: evidence from over 400 000 participants in 41 countries.

Author

Fernandez-Velasco, P., Coutrot, A., Oloye, H., Wiener, Jan M., Dalton, R. C., Holscher, C., Manley, E., Hornberger, M., Spiers, H. J., Fernandez-Velasco, P., Coutrot, A., Oloye, H., Wiener, Jan M., Dalton, R. C., Holscher, C., Manley, E., Hornberger, M., and Spiers, H. J.

Abstract

There is an active debate concerning the association of handedness and spatial ability. Past studies used small sample sizes. Determining the effect of handedness on spatial ability requires a large, cross-cultural sample of participants and a navigation task with real-world validity. Here, we overcome these challenges via the mobile app Sea Hero Quest. We analysed the navigation performance from 422 772 participants from 41 countries and found no reliable evidence for any difference in spatial ability between left- and right-handers across all countries. A small but growing gap in performance appears for participants over 64 years old, with left-handers outperforming right-handers. Further analysis, however, suggests that this gap is most likely due to selection bias. Overall, our study clarifies the factors associated with spatial ability and shows that left-handedness is not associated with either a benefit or a deficit in spatial ability.

44. Anaesthesia generates neuronal insulin resistance by inducing hypothermia

Author

Sutherland Calum, van Aalten Lidy, and Holscher Christian

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurophysiology and neuropsychology, QP351-495
Abstract

Abstract Background Anaesthesia is commonly employed prior to surgical investigations and to permit icv injections in rodents. Indeed it is standard practise in many studies examining the subsequent actions of hormones and growth factors on the brain. Recent evidence that the basal activity of specific intracellular signalling proteins can be affected by anaesthesia prompted us to examine the effect of anaesthesia not only on the basal activity but also the insulin sensitivity of the major insulin signalling pathways. Results We find that urethane- and ketamine-induced anaesthesia results in rapid activation of the phosphatidylinositol (PI) 3-kinase-protein kinase B (PKB) signalling pathway in the brain, increases tau phosphorylation while at the same time reducing basal activity of the Ras-ERK pathway. Subsequent injection of insulin does not alter the activity of either the PI 3-kinase or ERK signalling pathways, indicating a degree of neuronal molecular insulin resistance. However, if body temperature is maintained during anaesthesia then there is no alteration in the basal activity of these signalling molecules. Subsequent response of both pathways to insulin injection is restored. Conclusion The data is consistent with a hypothermia related alteration in neuronal signalling following anaesthesia, and emphasises the importance of maintaining the body temperature of rodents when monitoring insulin (or growth factor/neurotrophic agent) action in the brain of anesthetised rodents.

Published
2008
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45. Retraction.

Author

Holscher, C.

Subjects
*CORRECTION notices (Newspapers), *NEUROSCIENCES, *PERIODICALS
Abstract

Retracts data published in the July 1999 issue of the 'European Journal of Neuroscience,' in which the author asserted that LTP was blocked by 7-nitroindazole, following the use of a different experimental set-ups. Demonstration of non-blocking of 7-nitroindazole in subsequent experiments; Details of experimental method; Complexity of mechanisms involved; Absence of an explanation for the error.

Published
1999
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47. Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?

Author

Stefan Carver, Naghma Malik, Craig W. Ritchie, Sanara Raza, John E Harrison, Salman Karim, Gregor Russell, David J. Brooks, Clive Holmes, George Tadros, Gail Busza, Vandana Mate, Sajeev Kshemendran, Anthony Peter Passmore, Basil H. Ridha, Thalia van der Doef, Lucy Knight, Kehinde Junaid, Elizabeth Coulthard, Ben Underwood, Hilary Archer, Tricia Tan, Sharon Love, Zuzana Walker, Paul Koranteng, Ajayverma Macharouthu, Bernadette McGuinness, Andrew Donaldson, Simon Thacker, Clive Ballard, Grazia Daniela Femminella, Paul Edison, Valeria Calsolaro, Aparna Prasanna, Ramin Nilforooshan, Nicholas R Livingston, Christian Hölscher, Robert M. Lawrence, Carol Bannister, Brady McFarlane, Eleni Frangou, Femminella, G. D., Livingston, N. R., Raza, S., van der Doef, T., Frangou, E., Love, S., Busza, G., Calsolaro, V., Carver, S., Holmes, C., Ritchie, C. W., Lawrence, R. M., Mcfarlane, B., Tadros, G., Ridha, B. H., Bannister, C., Walker, Z., Archer, H., Coulthard, E., Underwood, B., Prasanna, A., Koranteng, P., Karim, S., Junaid, K., Mcguinness, B., Passmore, A. P., Nilforooshan, R., Macharouthu, A., Donaldson, A., Thacker, S., Russell, G., Malik, N., Mate, V., Knight, L., Kshemendran, S., Tan, T., Holscher, C., Harrison, J., Brooks, D. J., Ballard, C., and Edison, P.

Subjects
0301 basic medicine, medicine.medical_treatment, Type 2 diabetes, lcsh:RC346-429, 0302 clinical medicine, 11 Medical and Health Sciences, education.field_of_study, Brain, Alzheimer's disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Homeostatic model assessment, Life Sciences & Biomedicine, Alzheimer’s disease, Human, medicine.medical_specialty, Cognitive Neuroscience, Population, Clinical Neurology, Carbohydrate metabolism, Grey matter, lcsh:RC321-571, 03 medical and health sciences, Insulin resistance, Magnetic resonance imaging, SDG 3 - Good Health and Well-being, Alzheimer Disease, Fluorodeoxyglucose F18, Internal medicine, medicine, Humans, Positron emission tomography imaging, education, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Science & Technology, business.industry, Insulin, Research, Neurosciences, medicine.disease, Hyperintensity, 030104 developmental biology, Endocrinology, Glucose, Diabetes Mellitus, Type 2, Positron-Emission Tomography, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery
Abstract

Background Type 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. Methods In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. Results In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. Conclusions In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Published
2021
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48. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.

Author

Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG, Bomfim, Theresa R, Forny-Germano, Leticia, and Sathler, Luciana B

Abstract

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD. [ABSTRACT FROM AUTHOR]

Published
2012
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49. A Novel Retro-Inverso Peptide Inhibitor Reduces Amyloid Deposition, Oxidation and Inflammation and Stimulates Neurogenesis in the APPswe/PS1ΔE9 Mouse Model of Alzheimer’s Disease

Author

Vadivel Parthsarathy, Elisa Salvati, Christian Hölscher, David Allsop, Mark Taylor, Paula McClean, Claire Tinker, Oleg Kolosov, Glynn Jones, Massimo Masserini, Maria Gregori, Parthsarathy, V, Mcclean, P, Holscher, C, Taylor, M, Tinker, C, Jones, G, Kolosov, O, Salvati, E, Gregori, M, Masserini, M, and Allsop, D

Subjects
Male, Mouse, Long-Term Potentiation, Beta-Sheet Conformation, Plaque, Amyloid, Bioinformatics, medicine.disease_cause, Biochemistry, Amyloid beta-Protein Precursor, Mice, Drug Discovery, Neurobiology of Disease and Regeneration, Cells, Cultured, Multidisciplinary, Microglia, Chemistry, Neurodegeneration, Neurogenesis, Neurodegenerative Diseases, Animal Models, medicine.anatomical_structure, Neurology, Blood-Brain Barrier, Oligomer, Cerebral cortex, Medicine, Female, In-Vivo, Alzheimer's disease, Oxidation-Reduction, Protein Binding, Research Article, Biotechnology, Amyloid, Drugs and Devices, medicine.medical_specialty, Drug Research and Development, Curcumin, Science, Mice, Transgenic, Therapeutics, Blood–brain barrier, Permeability, Cell Line, Aggregation, Model Organisms, Alzheimer Disease, Internal medicine, medicine, Animals, Biology, Inflammation, Amyloid beta-Peptides, Protein, Dentate gyrus, Fibrillogenesi, medicine.disease, Disease Models, Animal, Oxidative Stress, Endocrinology, Dementia, Fibril Formation, Protein Multimerization, Peptides, Oxidative stress, Neuroscience
Abstract

Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr) that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer's disease. We have now attached a retro-inverted version of the HIV protein transduction domain 'TAT' to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH2) into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p

Published
2013
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50. Non-tuberculous mycobacterial bone and joint infections - a case series from a tertiary referral centre in Australia.

Author

Holscher C, Manzanero S, Hume A, Foster AL, Tetsworth K, and Chapman PR

Subjects
Humans, Male, Female, Middle Aged, Aged, Queensland epidemiology, Nontuberculous Mycobacteria isolation & purification, Adult, Prosthesis-Related Infections microbiology, Prosthesis-Related Infections therapy, Prosthesis-Related Infections diagnosis, Anti-Bacterial Agents therapeutic use, Arthritis, Infectious microbiology, Arthritis, Infectious diagnosis, Arthritis, Infectious therapy, Retrospective Studies, Australia epidemiology, Mycobacterium Infections, Nontuberculous diagnosis, Mycobacterium Infections, Nontuberculous therapy, Tertiary Care Centers, Osteomyelitis microbiology, Osteomyelitis diagnosis
Abstract

Background: Non-tuberculous mycobacteria (NTM) are rare causes of bone and joint infection (BJI) and there is limited evidence on which to base management decisions. This study describes 1 year of experience from a multi-disciplinary BJI team which collects data on all cases reviewed at a tertiary referral centre in Queensland, Australia., Methods: The database was interrogated for all cases in which NTM were recovered from operative samples. Individual chart review was performed to collect the details of each case., Results: A total of seven cases were managed between 1st February 2021 and 28th February 2022, comprising one patient with chronic osteomyelitis, three with fracture-related infections, two with prosthetic joint infections, and one with infection of a synthetic ligament graft. In contrast to pulmonary NTM infections, most patients were clinically well and immunocompetent, and most infections were propagated by direct inoculation. Time to diagnosis was unknown in three patients, with 1, 2, 2, and 5 months for the remaining four. Rapid growing NTM were diagnosed on routine cultures and specific mycobacterial cultures were confirmatory. Management was characterized by multiple stage surgical procedures and prolonged antimicrobial regimens., Conclusions: Antimicrobial complications were common; however, all patients were infection free at their latest follow up. Despite the inherent limitations, these results suggest that routinely ordering mycobacterial culture is of low yield. There is potential for shorter-term oral antimicrobial treatments. Prospective research is required to optimize treatment regimens and durations., (© 2024 The Author(s). ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Published
2024
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