Yang Sujeong, Hilton Sam, Alves João Nuno, Saksida Lisa M, Bussey Timothy, Matthews Russell T, Kitagawa Hiroshi, Spillantini Maria Grazia, Kwok Jessica C F, Fawcett James W
John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Department of Psychology, University of Cambridge, Cambridge, UK; Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
Neurobiol Aging. 2017 Nov;59:197-209. doi: 10.1016/j.neurobiolaging.2017.08.002. Epub 2017 Aug 9.
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.
硫酸软骨素蛋白聚糖（CSPGs）是神经元周围网（PNNs）的主要活性成分。用软骨素酶ABC消化CSPGs的糖胺聚糖链或通过转基因手段减弱PNNs，会导致成年中枢神经系统中物体识别记忆的延长以及各种形式可塑性的激活。CSPGs的抑制特性取决于其糖胺聚糖的硫酸化模式，其中硫酸软骨素4-硫酸酯（C4S）是最具抑制性的形式。在本研究中，我们测试了多种用于功能性阻断C4S的候选物，最终筛选出一种抗体Cat316，它能特异性识别C4S并阻断其对轴突生长的抑制作用。它还能部分阻断信号素3A与PNNs的结合并减弱PNNs的形成。我们询问将Cat316注入鼻周皮质是否会对记忆产生与软骨素酶ABC处理相同的效果。我们发现，用Cat316抗体掩盖C4S可将正常野生型小鼠的长期物体识别记忆延长至24小时，这与软骨素酶或转基因减弱PNNs的效果类似。然后，我们在神经退行性疾病模型中测试了Cat316恢复记忆的能力。表达P301S突变tau蛋白的小鼠在4个月大时表现出明显的物体识别记忆丧失。向鼻周皮质注射Cat316可使P301S小鼠在3小时时的物体识别恢复正常。这些数据表明，Cat316与细胞外基质中的C4S结合能够以与软骨素酶ABC消化相同的方式恢复可塑性和记忆。我们的结果表明，针对C4S的抗体可能是恢复神经退行性疾病中记忆功能的一种有效治疗方法。
