Inhibiting the Ca2+ Influx Induced by Human CSF

Cell Reports

卷:21

Henrik Zetterberg¹  Nick C. Fox²  Catherine F. Slattery²  Jonathan M. Schott²  Ross W. Paterson²  David Klenerman³  Anna Drews³  Wei-Hsin Chen³  Suman De³  Daniel R. Whiten³  Patrick Flagmeier³  David C. Wirthensohn³  Christopher M. Dobson³  Margarida Rodrigues³  Serge Muyldermans⁴  Cécile Vincke⁴  Sonia Gandhi⁵ 

[1] Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden;

[2] Dementia Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK;

[3] Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK;

[4] Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium;

[5] Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK;

关键词: neurodegenerative conditions;    Alzheimer’s disease;    cerebrospinal fluid;    beta amyloid;    oligomers;    clusterin;    antibodies;    single molecule imaging;    fluorescence measurements;    calcium influx;   

DOI  :  10.1016/j.celrep.2017.11.057

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown