HAPLN2 (hyaluronan and proteoglycan link protein 2) is an extracellular matrix protein that mediates binding of versican to hyaluronic acid, primarily functioning in central nervous system structural organization at nodes of Ranvier 1. In healthy brains, HAPLN2 supports neuronal conduction and CNS matrix stability 2. However, HAPLN2 exhibits pathological aggregation during brain aging, accumulating as sarkosyl-insoluble protein aggregates when microglial function declines and hyaluronic acid levels increase 1. These HAPLN2 oligomers trigger microglial inflammatory responses, contributing to cerebellar aging 1. Age-related HAPLN2 accumulation in oligodendrocytes impairs memory function; reducing elevated HAPLN2 levels restores synaptic plasticity and cognitive performance in aged mice 3. HAPLN2 overexpression also contributes to Parkinson's disease pathogenesis by promoting protein aggregation and dopaminergic neurodegeneration 4. Additionally, altered HAPLN2 splicing occurs in alcohol use disorder following PCBP1-mediated dysregulation, potentially impairing hippocampal function 5. HAPLN2 has been identified as a candidate biomarker in glioblastoma and Alzheimer's disease proteomic studies 67. These findings establish HAPLN2 as a key mediator linking extracellular matrix remodeling to age-related cognitive decline and neurodegeneration.