Inhibiting the Ca 2+ Influx Induced by Human CSF

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

Onderzoeksoutput: Articlepeer review

17 Citaten (Scopus)

Samenvatting

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 Ca 2+ 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 Ca 2+ 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. Drews et al. develop and implement sensitive in vitro assays to quantitatively measure the Ca 2+ influx caused by human cerebrospinal fluid. If a given chaperone, antibody, or nanobody is effective in reducing Ca 2+ influx, the authors determine what concentration is needed to prevent Ca 2+ influx.

Originele taal-2English
Pagina's (van-tot)3310-3316
Aantal pagina's7
TijdschriftCell Reports
Volume21
Nummer van het tijdschrift11
DOI's
StatusPublished - 12 dec 2017

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