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

Astrocytes are central to central nervous system (CNS) homeostasis and memory consolidation. They also display remarkably heterogeneous morphological phenotypes, functions and molecular profiles between and within distinct regions of the human brain. Yet, their role in regional vulnerability in neurodegenerative diseases (NDDs) remains poorly understood. To elucidate this subregional heterogeneity of astrocytes in the hippocampus and parahippocampal cortex and its implication for neurodegeneration, we employed high-content neuropathology, integrating chromogenic immunohistochemistry (cIHC) and digital pathology, to map and quantify the expression of functional astrocytic markers (GFAP, ALDH1L1, AQP4, GPC5 and ALDH7A1) of healthy individuals, of patients with Alzheimer’s disease (AD) or Parkinson’s disease with dementia (PDD). We found that astrocytic markers followed distinct expression patterns in AD and PDD. In AD, GFAP was strongly reduced in specific hippocampal regions, whereas AQP4 was increased and GPC5 expression, although regionally stable, was locally associated with amyloid and tau pathology. In PDD, astrocytic responses were characterized by selective decreases in ALDH1L1 and ALDH7A1, with GFAP and GPC5 remaining largely unaffected. Notably, GFAP and GPC5 expression delineated distinct astrocytic subtypes that were differentially distributed across hippocampal subfields and showed specific responses to AD and PD pathologies. These findings provide new insights into the landscape of astrocytic heterogeneity in the human hippocampus and beyond, revealing disease- and region-specific astrocytic signatures. Importantly, they underscore the value of incorporating novel markers such as GPC5 to fully capture astrocytic diversity and to better understand astrocyte contributions to neurodegeneration.