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.

Department of Biochemistry Kobe Pharmaceutical University Kobe Japan

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Neuroscience and Physiology State University of New York Upstate Medical University Syracuse NY USA

Department of Psychology University of Cambridge Cambridge UK; Molecular Medicine Research Group Robarts Research Institute Schulich School of Medicine and Dentistry Western University London Ontario Canada

John Van Geest Centre for Brain Repair University of Cambridge Cambridge UK; Department of Clinical Neurosciences University of Cambridge Cambridge UK

John Van Geest Centre for Brain Repair University of Cambridge Cambridge UK; Department of Clinical Neurosciences University of Cambridge Cambridge UK; Centre for Reconstructive Neurosciences Institute of Experimental Medicine ASCR Prague 4 Czech Republic

John Van Geest Centre for Brain Repair University of Cambridge Cambridge UK; Department of Clinical Neurosciences University of Cambridge Cambridge UK; School of Biomedical Sciences University of Leeds Leeds UK; Centre for Reconstructive Neurosciences Institute of Experimental Medicine ASCR Prague 4 Czech Republic

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