Graduate School of Bioagricultural Sciences, Nagoya University, Furocho, Chikusa-Ku, Nagoya 464-8601, Japan.
Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwaicho, Fuchu, Tokyo 183-8509, Japan.
Biochim Biophys Acta Gen Subj. 2021 Feb;1865(2):129804. doi: 10.1016/j.bbagen.2020.129804. Epub 2020 Nov 28.
Perineuronal nets (PNNs) are insoluble aggregates of extracellular matrix molecules in the brain that consist of hyaluronan (HA) and chondroitin sulfate proteoglycans (CSPGs). PNNs promote the acquisition and storage of memories by stabilizing the formation of synapses in the adult brain. Although the deterioration of PNNs has been suggested to contribute to the age-dependent decline in brain function, the molecular mechanisms underlying age-related changes in PNNs remain unclear.
The amount and solubility of PNN components were investigated by sequential extraction followed by a disaccharide analysis and immunoblotting. We examined the interaction between HA and aggrecan, a major HA-binding CSPG, by combining mass spectrometry and pull-down assays.
The solubility and amount of HA increased in the brain with age. Among several CSPGs, the solubility of aggrecan was selectively elevated during aging. In contrast to alternations in biochemical properties, the expression of PNN components at the transcript level was not markedly changed by aging. The increased solubility of aggrecan was not due to the loss of HA-binding properties. Our results indicated that the degradation of high-molecular-mass HA induced the release of the HA-aggrecan complex from PNNs in the aged brain.
The present study revealed a novel mechanism underlying the age-related deterioration of PNNs in the brain.
周围神经毡（PNNs）是大脑中细胞外基质分子的不溶性聚集体，由透明质酸（HA）和软骨素硫酸盐蛋白聚糖（CSPGs）组成。PNNs 通过稳定成年大脑中突触的形成来促进记忆的获得和存储。尽管 PNNs 的退化被认为有助于大脑功能随年龄的下降，但 PNNs 随年龄相关变化的分子机制仍不清楚。
通过顺序提取 followed by a disaccharide analysis and immunoblotting 来研究 PNN 成分的含量和溶解度。我们通过结合质谱和下拉测定法来研究 HA 和聚集蛋白聚糖（一种主要的 HA 结合 CSPG）之间的相互作用。
随着年龄的增长，大脑中 HA 的溶解度和含量增加。在几种 CSPGs 中，聚集蛋白聚糖的溶解度在衰老过程中选择性升高。与生化特性的改变相反，PNN 成分的转录水平表达在衰老过程中没有明显变化。聚集蛋白聚糖溶解度的增加不是由于丧失了与 HA 结合的特性。我们的结果表明，高分子质量 HA 的降解诱导了老年大脑中 HA-聚集蛋白聚糖复合物从 PNNs 中的释放。
本研究揭示了大脑中 PNNs 随年龄相关恶化的新机制。
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