By Caroline McNinch^1,2, Nicholas Mitsios^1, Tianyu Zheng¹, Jan Mulder¹

¹Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden,

²Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis

School of Medicine, Missouri, USA

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https://doi.org/10.55894/dv5.13

Abstract

BAG3 is a stress-responsive co-chaperone implicated in protein quality control and neurodegenerative

disease, yet its cell-type specificity and pathological relevance in the adult human brain remain poorly defined.

This paper provides a comprehensive protein-level characterization of BAG3 and its interaction with the

CASA component HSPB8 in post-mortem human cortex from healthy and neurodegenerative donors. Using

multiplex immunofluorescence, we demonstrate that BAG3 is astrocyte-specific and spans multiple astrocyte

subpopulations. BAG3-HSPB8 exhibits distinct subcellular compartmentalization within astrocyte somas,

suggesting possible CASA-independent functions of BAG3 in astrocyte processes. In Alzheimer’s disease,

BAG3 expression near amyloid-beta plaques varies with plaque morphology and activity. BAG3-HSPB8 is

enriched near active, dense-core plaques, while BAG3 is present without detectable HSPB8 enrichment near

diffuse plaques, suggesting an alternative function. Together, these findings identify astrocytic BAG3 as a

context-dependent regulator of Aβ plaques consistent with dual neuroprotective and potentially pathogenic

roles.Clinic who received angiography between May 1981 and September 1984. Each patient ID includes the

individual patients’ vitals and medical history.