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The antigen-binding fragment of human gamma immunoglobulin prevents amyloid beta-peptide folding into beta-sheet to form oligomers
Valls Comamala, Victòria; Guivernau, Biuse; Bonet, Jaume; Puig, Marta; Peralvarez Marin, Alex; Palomer, Ernest; Fernàndez Busquets, Xavier; Altafaj, Xavier; Tajes, Marta; Puig Pijoan, Albert; Vicente, Rubén; Oliva, Baldomero; Munoz, Francisco J.
The amyloid beta-peptide (Abeta) plays a leading role in Alzheimer's disease (AD) physiopathology. Even though monomeric forms of Abeta are harmless to cells, Abeta can aggregate into beta-sheet oligomers and fibrils, which are both neurotoxic. Therefore, one of the main therapeutic approaches to cure or delay AD onset and progression is targeting Abeta aggregation. In the present study, we show that a pool of human gamma immunoglobulins (IgG) protected cortical neurons from the challenge with Abeta oligomers, as assayed by MTT reduction, caspase-3 activation and cytoskeleton integrity. In addition, we report the inhibitory effect of IgG on Abeta aggregation, as shown by Thioflavin T assay, size exclusion chromatography and atomic force microscopy. Similar results were obtained with Palivizumab, a human anti-sincitial virus antibody. In order to dissect the important domains, we cleaved the pool of human IgG with papain to obtain Fab and Fc fragments. Using these cleaved fragments, we functionally identified Fab as the immunoglobulin fragment inhibiting Abeta aggregation, a result that was further confirmed by an in silico structural model. Interestingly, bioinformatic tools show a highly conserved structure able to bind amyloid in the Fab region. Overall, our data strongly support the inhibitory effect of human IgG on Abeta aggregation and its neuroprotective role.
Malaltia d'Alzheimer
Immunoglobulines
Malalties neurodegeneratives
Alzheimer's disease
Immunoglobulins
Neurodegenerative Diseases
cc by (c) Valls-Comamala et al., 2017
http://creativecommons.org/licenses/by/3.0/es/
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