Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration

NEUROBIOLOGY OF AGING

卷:59

Article

Yang, Sujeong^1,2  Hilton, Sam^1,2  Alves, Joao Nuno^1,2  Saksida, Lisa M.^3,4  Bussey, Timothy^3,4  Matthews, Russell T.⁵  Kitagawa, Hiroshi⁶  Spillantini, Maria Grazia²  Kwok, Jessica C. F.^1,2,7,8  Fawcett, James W.^1,2,8 

[1] Univ Cambridge, John Van Geest Ctr Brain Repair, Cambridge, England

[2] Univ Cambridge, Dept Clin Neurosci, Cambridge, England

[3] Univ Cambridge, Dept Psychol, Cambridge, England

[4] Western Univ, Schulich Sch Med & Dent, Mol Med Res Grp, Robarts Res Inst, London, ON, Canada

[5] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA

[6] Kobe Pharmaceut Univ, Dept Biochem, Kobe, Hyogo, Japan

[7] Univ Leeds, Sch Biomed Sci, Leeds, W Yorkshire, England

[8] Inst Expt Med ASCR, Ctr Reconstruct Neurosci, Prague 4, Czech Republic

关键词: Perineuronal nets;    CSPGs;    Object recognition memory;    Plasticity;    Alzheimer's disease;   

DOI  :  10.1016/j.neurobiolaging.2017.08.002

来源: Elsevier

【 摘 要 】

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 anti-bodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders. (C) 2017 Elsevier Inc. All rights reserved.

【 授权许可】

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