Hyaluronan degradation and release of a hyaluronan-aggrecan complex from perineuronal nets in the aged mouse brain

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.