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Juliet A Moncaster, Srikant Sarangi, Olga Minaeva, Xiao-lei Zhang, Robin Altman, Rajendra Gangalum, John Sullivan, Cidi Chen, Bertrand Huber, Ella Zeldich, Carmela Abraham, Suraj P Bhat, John Voss, Dean Hartley, Patric K Stanton, Lee E Goldstein; αB-Crystallin Potentiates Alzheimer’s Disease Aβ Neurotoxicity by Hetero-Oligomeric Stabilization. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2089.
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We previously reported Aβ accumulation in lenses from patients Alzheimer’s Disease (AD) (Goldstein et al., 2003) and Down syndrome (Moncaster et al., 2010), a common chromosomal disorder in which age-related Aβ brain pathology is an invariant feature. Aβ co-localized with αB-crystallin in these lenses. Here we investigate the molecular mechanisms underpinning αB-crystallin interactions with Aβ and implications for AD pathogenesis.
Immunohistofluorescence, Confocal Microscopy, Immunogold electron microscopy, SDS-page and immunoblotting, electron paramagnetic resonance spectroscopy (EPR), quasi-elastic light scattering (QLS) spectroscopy, cell and organotypic slice culture, LDH and Propidium iodide assays.
Electron paramagnetic resonance spectroscopy revealed that αB-crystallin dynamically interacts with and binds to Aβ in vitro in concordance with previous findings. Quasi-elastic light scattering spectroscopy showed that αB-crystallin suppresses formation of high molecular weight Aβ aggregates by stabilizing soluble hetero-oligomeric complexes. However, whilst co-incubation of αB-crystallin and Aβ suppressed Aβ fibrillogenesis, αB-crystallin potentiated Aβ neurotoxicity in mouse primary neurons and organotypic rat hippocampus slice culture as detected by LDH and Propidium Iodide assays.
These results indicate that αB-crystallin potentiates Aβ neurotoxicity by stabilizing soluble hetero-oligomers.
This is a 2021 ARVO Annual Meeting abstract.
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