αB-Crystallin interaction with Alzheimer’s Disease Amyloid-β potentiates Aβ-Mediated Neurotoxicity

Abstract

Purpose: Alzheimer’s disease neuritic plaque is composed of amyloid-β (Aβ) and also contains low molecular weight chaperones including αB-crystallin. We investigated the hypothesis that these ubiquitous molecular chaperones might potentiate pathogenic protein aggregation and neurotixicity by interacting with Aβ.

Methods: Immunogold electron microscopy, SDS-page and immunoblotting, spectral reflectance imaging biosensor, electrophysiology, cell and organotypic slice culture.

Results: Immunohistochemical analysis of human Alzheimer’s disease brain revealed co-localization of human Aβ and human αB-crystallin in neuritic plaque. Immunohistochemistry and immunoblotting analysis demonstrated that αB-crystalllin is expressed and secreted from astrocytes through an exosomal pathway. Immunogold electron microscopic experiments showed that human αB-crystalllin arrested human Aβ peptide fibrillogenesis and sequestered this amyloidogenic peptide into soluble complexes. αB-Crystallin dose-dependently potentiated Aβ cytotoxicity in SH-SY5Y human neuroblastoma cells.

Conclusions: Our data show that αB-crystallin is expressed and secreted by astrocytes, binds to Aβ and enhances its toxicity to both synaptic function and neuronal survival, probably by increasing the concentration of low molecular weight soluble Aβ complexes. These properties of αB-crystallin suggest an antagonistic pleiotropy that may be critical to the pathogenesis of Alzheimer’s disease.