Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration
Authors
Yang, Su-Jeong
Hilton, Sam
Alves, João Nuno
Saksida, Lisa
Bussey, Timothy
Matthews, Russell T
Kitagawa, Hiroshi
Kwok, Jessica CF
Publication Date
2017-11Journal Title
Neurobiology of Aging
ISSN
0197-4580
Publisher
Elsevier
Volume
59
Pages
197-209
Language
eng
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Yang, S., Hilton, S., Alves, J. N., Saksida, L., Bussey, T., Matthews, R. T., Kitagawa, H., et al. (2017). Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration. Neurobiology of Aging, 59 197-209. https://doi.org/10.1016/j.neurobiolaging.2017.08.002
Abstract
Chondroitin sulfate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult central nervous system. The inhibitory properties of the CSPGs depend on the pattern of sulfation of their glycosaminoglycans, with chondroitin 4-sulfate (C4S) being the most inhibitory form. In this study, we tested a number of candidates for functional blocking of C4S, leading to selection of an antibody, Cat316, which specifically recognizes C4S and blocks its inhibitory effects on axon growth. It also partly blocks binding of semaphorin 3A to PNNs and attenuates PNN formation. We asked whether injection of Cat316 into the perirhinal cortex would have the same effects on memory as chondroitinase ABC treatment. We found that masking C4S with the Cat316 antibody extended long-term object recognition memory in normal wild-type mice to 24 hours, similarly to chondroitinase or transgenic PNN attenuation. We then tested Cat316 for restoration of memory in a neurodegeneration model. Mice expressing tau with the P301S mutation showed profound loss of object recognition memory at 4 months of age. Injection of Cat316 into the perirhinal cortex normalized object recognition at 3 hours in P301S mice. These data indicate that Cat316 binding to C4S in the extracellular matrix can restore plasticity and memory in the same way as chondroitinase ABC digestion. Our results suggest that antibodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders.
Keywords
Perineuronal nets, CSPGs, Object recognition memory, Plasticity, Alzheimer's disease
Sponsorship
This work was supported by the ERC advanced grant ECM Neuro (294502), by a fellowship to SY from Alzheimer's Research UK (ARUK-RF2016A-1), and by the NIHR Cambridge Biomedical Research Centre.
Funder references
European Research Council (294502)
MRC (MR/R004544/1)
Identifiers
External DOI: https://doi.org/10.1016/j.neurobiolaging.2017.08.002
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275933
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/