GPC5 expression highlights astrocytic heterogeneity and divergent hippocampal responses in Alzheimer's and Parkinson's Dementia

Abstract

Regional heterogeneity of astrocytes and neurons is increasingly recognised as a determinant of selective vulnerability in neurodegeneration, yet the molecular signatures underlying this specificity remain poorly defined. Glypican-5 (GPC5), a heparan sulfate proteoglycan expressed mainly by astrocytes, contributes to synaptic organisation and circuit stability, whose disruption may undermine astrocyte-neuron crosstalk and contribute to selective neuronal loss in neurodegenerative diseases. Using multiplex chromogenic immunohistochemistry, in situ hybridization and digital pathology, we mapped GPC5 expression across the hippocampus and parahippocampal cortex in post-mortem tissue from non-demented control (CTL), Alzheimers disease (AD) and Parkinsons disease with dementia (PDD) cases. In CTL brains, GPC5 labelled spatially restricted populations of astrocytes and pyramidal neurons organized according to hippocampal subfield and laminar architecture. GPC5-positive astrocytes co-expressed canonical markers but represented a more restricted population while GPC5 protein was enriched at synapse-rich regions of the outer molecular layer of the dentate gyrus. In AD and PDD, regional distribution patterns of GPC5 were distinct from canonical astrocyte markers including GFAP, AQP4 and ALDH1L1. In PDD, GPC5 distribution was largely preserved. In AD, GPC5 underwent selective redistribution with a significant loss of the staining in the dentate gyrus, and an accumulation on amyloid plaques, putatively secreted by plaque-associated astrocytes, and on neurofibrillary tangles, likely of neuronal and astrocytic origin These findings reveal disease- and region-specific remodelling of a spatially organised astrocyte-neuron system and establish GPC5 as a molecularly distinct responder to AD pathology.