Inhibiting the Ca2+ Influx Induced by Human CSF
One potential therapeutic strategy for Alzheimer’s disease (AD) is to use antibodies that bind to small soluble protein aggregates to reduce their toxic effects. However, these therapies are rarely tested in human CSF before clinical trials because of the lack of sensitive methods that enable the me...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-12-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717317096 |
| _version_ | 1818230010376355840 |
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| author | Anna Drews Suman De Patrick Flagmeier David C. Wirthensohn Wei-Hsin Chen Daniel R. Whiten Margarida Rodrigues Cécile Vincke Serge Muyldermans Ross W. Paterson Catherine F. Slattery Nick C. Fox Jonathan M. Schott Henrik Zetterberg Christopher M. Dobson Sonia Gandhi David Klenerman |
| author_facet | Anna Drews Suman De Patrick Flagmeier David C. Wirthensohn Wei-Hsin Chen Daniel R. Whiten Margarida Rodrigues Cécile Vincke Serge Muyldermans Ross W. Paterson Catherine F. Slattery Nick C. Fox Jonathan M. Schott Henrik Zetterberg Christopher M. Dobson Sonia Gandhi David Klenerman |
| author_sort | Anna Drews |
| collection | DOAJ |
| description | One potential therapeutic strategy for Alzheimer’s disease (AD) is to use antibodies that bind to small soluble protein aggregates to reduce their toxic effects. However, these therapies are rarely tested in human CSF before clinical trials because of the lack of sensitive methods that enable the measurement of aggregate-induced toxicity at low concentrations. We have developed highly sensitive single vesicle and single-cell-based assays that detect the Ca2+ influx caused by the CSF of individuals affected with AD and healthy controls, and we have found comparable effects for both types of samples. We also show that an extracellular chaperone clusterin; a nanobody specific to the amyloid-β peptide (Aβ); and bapineuzumab, a humanized monoclonal antibody raised against Aβ, could all reduce the Ca2+ influx caused by synthetic Aβ oligomers but are less effective in CSF. These assays could be used to characterize potential therapeutic agents in CSF before clinical trials. |
| first_indexed | 2024-12-12T10:27:42Z |
| format | Article |
| id | doaj.art-3fb486ca17474719aec0f211bac9ee41 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T10:27:42Z |
| publishDate | 2017-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3fb486ca17474719aec0f211bac9ee412022-12-22T00:27:25ZengElsevierCell Reports2211-12472017-12-0121113310331610.1016/j.celrep.2017.11.057Inhibiting the Ca2+ Influx Induced by Human CSFAnna Drews0Suman De1Patrick Flagmeier2David C. Wirthensohn3Wei-Hsin Chen4Daniel R. Whiten5Margarida Rodrigues6Cécile Vincke7Serge Muyldermans8Ross W. Paterson9Catherine F. Slattery10Nick C. Fox11Jonathan M. Schott12Henrik Zetterberg13Christopher M. Dobson14Sonia Gandhi15David Klenerman16Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumDementia Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UKDementia Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UKDementia Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UKDementia Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UKClinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Mölndal, SwedenDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKSobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UKDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKOne potential therapeutic strategy for Alzheimer’s disease (AD) is to use antibodies that bind to small soluble protein aggregates to reduce their toxic effects. However, these therapies are rarely tested in human CSF before clinical trials because of the lack of sensitive methods that enable the measurement of aggregate-induced toxicity at low concentrations. We have developed highly sensitive single vesicle and single-cell-based assays that detect the Ca2+ influx caused by the CSF of individuals affected with AD and healthy controls, and we have found comparable effects for both types of samples. We also show that an extracellular chaperone clusterin; a nanobody specific to the amyloid-β peptide (Aβ); and bapineuzumab, a humanized monoclonal antibody raised against Aβ, could all reduce the Ca2+ influx caused by synthetic Aβ oligomers but are less effective in CSF. These assays could be used to characterize potential therapeutic agents in CSF before clinical trials.http://www.sciencedirect.com/science/article/pii/S2211124717317096neurodegenerative conditionsAlzheimer’s diseasecerebrospinal fluidbeta amyloidoligomersclusterinantibodiessingle molecule imagingfluorescence measurementscalcium influx |
| spellingShingle | Anna Drews Suman De Patrick Flagmeier David C. Wirthensohn Wei-Hsin Chen Daniel R. Whiten Margarida Rodrigues Cécile Vincke Serge Muyldermans Ross W. Paterson Catherine F. Slattery Nick C. Fox Jonathan M. Schott Henrik Zetterberg Christopher M. Dobson Sonia Gandhi David Klenerman Inhibiting the Ca2+ Influx Induced by Human CSF Cell Reports neurodegenerative conditions Alzheimer’s disease cerebrospinal fluid beta amyloid oligomers clusterin antibodies single molecule imaging fluorescence measurements calcium influx |
| title | Inhibiting the Ca2+ Influx Induced by Human CSF |
| title_full | Inhibiting the Ca2+ Influx Induced by Human CSF |
| title_fullStr | Inhibiting the Ca2+ Influx Induced by Human CSF |
| title_full_unstemmed | Inhibiting the Ca2+ Influx Induced by Human CSF |
| title_short | Inhibiting the Ca2+ Influx Induced by Human CSF |
| title_sort | inhibiting the ca2 influx induced by human csf |
| topic | neurodegenerative conditions Alzheimer’s disease cerebrospinal fluid beta amyloid oligomers clusterin antibodies single molecule imaging fluorescence measurements calcium influx |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717317096 |
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