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

Tomohiro Umeda, Takami Tomiyama*, Naomi Sakama, Saya Tanaka, Mary P. Lambert, William L. Klein, Hiroshi Mori

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

168 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1031-1042
Number of pages12
JournalJournal of Neuroscience Research
Volume89
Issue number7
DOIs
StatePublished - Jul 2011

Keywords

  • APP E693Δ mutation
  • Alzheimer's disease
  • Transgenic mouse

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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