Intraneuronal Amyloid β Oligomers Cause Cell Death Via Endoplasmic Reticulum Stress, Endosomal/Lysosomal Leakage, and Mitochondrial Dysfunction In Vivo

Intraneuronal accumulation of amyloid beta (A beta) is an early pathological change in Alzheimer's disease. Previously, we showed that the E693 Delta mutation (referred to as the Osaka mutation) of amyloid precursor protein (APP) caused intracellular accumulation of A beta oligomers and apoptosis in transfected COS-7 cells. We also showed that transgenic mice expressing APP(E693 Delta) (APP(OSK)) displayed both an age-dependent accumulation of intraneuronal A beta oligomers from 8 months of age and apparent neuronal loss in the hippocampus at 24 months of age. These findings indicate that intraneuronal A beta oligomers cause cell death, but the mechanism of this process remains unclear. Accordingly, here we investigated the subcellular localization and toxicity of intraneuronal A beta oligomers in APP(OSK)-transgenic mice. We found A beta 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 A beta oligomers cause cell death by inducing ER stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo. (C) 2011 Wiley-Liss, Inc.