The mechanisms of perineuronal net abnormalities in contributing aging and neurological diseases

The perineuronal net (PNN) is a highly latticed extracellular matrix in the central nervous system, which is composed of hyaluronic acid, proteoglycan, hyaluronan and proteoglycan link protein (Hapln), and tenascin. PNN is predominantly distributed in GABAergic interneurons expressing Parvalbumin (PV) and plays a critical role in synaptic function, learning and memory, oxidative stress, and inflammation. In addition, PNN's structure and function are also modulated by a variety of factors, including protein tyrosine phosphatase σ (PTPσ), orthodenticle homeo-box 2 (Otx2), and erb-b2 receptor tyrosine kinase 4 (ErbB4). Glycosaminoglycan (GAG), a component of proteoglycan, also influences PNN through its sulfate mode. PNN undergoes abnormal changes during aging and in various neurological diseases, such as Alzheimer's disease, Parkinson's disease, schizophrenia, autism spectrum disorder, and multiple sclerosis. Nevertheless, there is limited report on the relationship between PNN and aging or age-related neurological diseases. This review elaborates on the mechanisms governing PNN regulation and summarizes how PNN abnormalities contribute to aging and neurological diseases, offering insights for potential treatments.