alexa Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal lysosomal leakage, and mitochondrial dysfunction in vivo.


Journal of Gerontology & Geriatric Research

Author(s): Umeda T, Tomiyama T, Sakama N, Tanaka S, Lambert MP,

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Abstract Intraneuronal accumulation of amyloid β (Aβ) is an early pathological change in Alzheimer's disease. Previously, we showed that the E693Δ mutation (referred to as the "Osaka" mutation) of amyloid precursor protein (APP) caused intracellular accumulation of Aβ oligomers and apoptosis in transfected COS-7 cells. We also showed that transgenic mice expressing APP(E693Δ) (APP(OSK) ) displayed both an age-dependent accumulation of intraneuronal Aβ oligomers from 8 months of age and apparent neuronal loss in the hippocampus at 24 months of age. These findings indicate that intraneuronal Aβ oligomers cause cell death, but the mechanism of this process remains unclear. Accordingly, here we investigated the subcellular localization and toxicity of intraneuronal Aβ oligomers in APP(OSK) -transgenic mice. We found Aβ oligomer accumulation in the endoplasmic reticulum (ER), endosomes/lysosomes, and mitochondria in hippocampal neurons of 22-month-old mice. We also detected up-regulation of Grp78 and HRD1 (an E3 ubiquitin ligase), leakage of cathepsin D from endosomes/lysosomes into cytoplasm, cytochrome c release from mitochondria, and activation of caspase-3 in the hippocampi of 18-month-old mice. Collectively, our findings suggest that intraneuronal Aβ oligomers cause cell death by inducing ER stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo. © 2011 Wiley-Liss, Inc. Copyright © 2011 Wiley-Liss, Inc. This article was published in J Neurosci Res and referenced in Journal of Gerontology & Geriatric Research

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