αB-Crystallin Potentiates Alzheimer's Disease Amyloid-β (Aβ) Neurotoxicity And Impairment Of Synaptic Long-Term Potentiation (LTP)

Abstract

Purpose: : Azheimer’s disease (AD) is characterized by AD-linked amyloid pathology in brain and lens (Goldstein et al., 2003; Moncaster et al., PLoS One, 2010). Amyloid lesions in both compartments are composed of amyloid-β (Aβ) and small heat shock proteins, including αB-crystallin (αBC). We previously reported that human Aβ (hAβ) binds human αBC (hαBC) with high affinity (Kapp ~20 nM) and forms hetero-oligomeric complexes (~5-50 micron cross section) that scatter light (Goldstein et al., Lancet, 2003). Given the highly toxic nature of soluble oligomers of hAβ, we investigated the hypothesis that interaction of hαBC with hAβ might potentiate, rather than ameliorate, the toxic effects of hAβ on synaptic long-term potentiation (LTP) and neuronal viability.

Methods: : Immunogold EM, SDS-PAGE, immunoblotting, spectral reflectance imaging, neuronal cell culture, hippocampal organotypic slice culture, hippocampal electrophysiology, electron paramagnetic resonance (EPR).

Results: : Analysis of human AD brain revealed co-localization of hAβ and hαBC in neuritic plaque. Immunogold EM and spectral reflectance imaging experiments showed that hαBC arrests hAβ fibrillogenesis and sequesters this amyloidogenic peptide into soluble complexes. EPR analysis revealed functional interaction between hAβ and hαBC as well as stabilization of soluble disordered hAβ aggregates. hαBC dose-dependently potentiated hAβ-induced cytotoxicity in SH-SY5Y neuroblastoma cell culture. In acute hippocampal organotypic slice culture, hαBC potentiated hAβ-mediated pyramidal cell death and markedly enhanced hAβ-induced impairment of long-term potentiation (LTP) of Schaffer collateral-CA1 synaptic transmission.

Conclusions: : These results demonstrate that hαBC interacts with hAβ and exacerbates the toxic effects of hAβ on synaptic plasticity and neuronal survival. This toxic gain of function may be mediated by hαBC stabilization of potently neurotoxic soluble hAβ oligomeric complexes. Thus, hαBC chaperone activity may have antagonistically pleiotropic effects on critical biological substrates underpinning memory dysfunction and neurodegeneration in AD and other neurodegenerative disorders.

Keywords: protein structure/function • pathobiology • pathology: human