Foscarin Simona, Raha-Chowdhury Ruma, Fawcett James W, Kwok Jessica C F
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0PY, United Kingdom.
The Prague Centre of Reconstructive Neuroscience, Institute of Experimental Medicine AS CR, 14220 Prague 4, Czech Republic.
Aging (Albany NY). 2017 Jun 28;9(6):1607-1622. doi: 10.18632/aging.101256.
Chondroitin sulfate (CS) proteoglycans in perineuronal nets (PNNs) from the central nervous system (CNS) are involved in the control of plasticity and memory. Removing PNNs reactivates plasticity and restores memory in models of Alzheimer's disease and ageing. Their actions depend on the glycosaminoglycan (GAG) chains of CS proteoglycans, which are mainly sulfated in the 4 (C4S) or 6 (C6S) positions. While C4S is inhibitory, C6S is more permissive to axon growth, regeneration and plasticity. C6S decreases during critical period closure. We asked whether there is a late change in CS-GAG sulfation associated with memory loss in aged rats. Immunohistochemistry revealed a progressive increase in C4S and decrease in C6S from 3 to 18 months. GAGs extracted from brain PNNs showed a large reduction in C6S at 12 and 18 months, increasing the C4S/C6S ratio. There was no significant change in mRNA levels of the chondroitin sulfotransferases. PNN GAGs were more inhibitory to axon growth than those from the diffuse extracellular matrix. The 18-month PNN GAGs were more inhibitory than 3-month PNN GAGs. We suggest that the change in PNN GAG sulfation in aged brains renders the PNNs more inhibitory, which lead to a decrease in plasticity and adversely affect memory.
中枢神经系统（CNS）中神经周网（PNNs）里的硫酸软骨素（CS）蛋白聚糖参与可塑性和记忆的调控。在阿尔茨海默病和衰老模型中，去除神经周网可重新激活可塑性并恢复记忆。它们的作用取决于CS蛋白聚糖的糖胺聚糖（GAG）链，这些链主要在4位（C4S）或6位（C6S）硫酸化。虽然C4S具有抑制作用，但C6S对轴突生长、再生和可塑性更具容许性。C6S在关键期关闭期间减少。我们探究了老年大鼠中与记忆丧失相关的CS-GAG硫酸化是否存在后期变化。免疫组织化学显示，从3个月到18个月，C4S逐渐增加，C6S逐渐减少。从脑PNNs中提取的GAGs在12个月和18个月时C6S大幅减少，C4S/C6S比值增加。硫酸软骨素硫酸转移酶的mRNA水平没有显著变化。PNN GAGs比来自弥散细胞外基质的GAGs对轴突生长的抑制作用更强。18个月大的PNN GAGs比3个月大的PNN GAGs抑制作用更强。我们认为，老年大脑中PNN GAG硫酸化的变化使PNNs的抑制作用更强，这导致可塑性降低并对记忆产生不利影响。
