αB-Crystallin secretion from astrocytes and its implications for Alzheimer’s Disease

Abstract

Purpose: Alzheimer’s disease neuritic plaque in the brain is composed of amyloid-β (Aβ) and also contains low molecular weight chaperones including αB-crystallin. We investigated the hypotheses that αB-crystallin is secreted by astrocytes and might potentiate pathogenic protein aggregation by interacting with human amyloid-β in Alzheimer's disease.

Methods: Immunocytochemistry, immunogold electron microscopy, SDS-PAGE, immunoblotting, electrophysiology, cell and organotypic slice culture.

Results: Immunohistochemical analysis of human Alzheimer’s disease brain revealed co-localization of human Aβ (hAβ), human αB-crystallin and activated astrocytes in neuritic plaques. We investigated the source of the αB-crystallin and hypothesized it to be the surrounding activated astrocytes. In order to address this, we studied an astrocytic cell line and rat primary astrocytes. We found that αB-crystallin was expressed and secreted by astrocytes. Furthermore, we demonstrate that the resulting αB-crystallin that accumulates around the neuritic plaques binds to hAβ and causes neurotoxicity to neuronal cells and impairs synaptic function.

Conclusions: We demonstrate that αB-crystallin is generated and secreted from astrocytes. Furthermore, our data show that the αB-crystallin binds to hAβ and enhances the toxicity of hAβ to both synaptic function and neuronal survival therefore playing a role in the pathogenesis of Alzheimer’s disease.

Keywords: 488 crystallins • 429 astrocyte • 636 pathobiology