The E693Δ Mutation in Amyloid Precursor Protein Increases Intracellular Accumulation of Amyloid β Oligomers and Causes Endoplasmic Reticulum Stress-Induced Apoptosis in Cultured Cells

The E693 Delta mutation within the amyloid precursor protein (APP) has been suggested to cause dementia via the enhanced formation of synaptotoxic amyloid beta (A beta) oligomers. However, this mutation markedly decreases A beta secretion, implying the existence of an additional mechanism of neuronal dysfunction that is Independent of extracellular A beta. We therefore examined the effects of this mutation on both APP processing to produce A beta as well as subcellular localization and accumulation of A beta in transfected HEK293 and COS-7 cells. Both beta- and gamma-cleavage of mutant APP increased, indicating a lack of inhibition in A beta production. Instead, this mutation promoted A beta accumulation within cells, including the endoplasmic reticulum (ER), Golgi apparatus, early and late endosomes, lysosomes, and autophagosomes, all of which have been proposed as intracellular sites of A beta generation and/or degradation, suggesting impairment of APP/A beta trafficking. Notably, the intracellular mutant A beta was found to predominantly form oligomers. Concomitant with this accumulation, the ER stress markers Grp78 and phosphorylated eIF-2 alpha were both strongly induced. Furthermore, the activation of caspase-4 and -3 as well as DNA fragmentation were detected In these cells. These results, suggest that mutant AV induces alteration of A beta trafficking and subsequent ER stress-induced apoptosis via enhancement of its intracellular oligomerization. Our findings suggest that A beta oligomers exhibit toxicity in the extra-cellular space and within the cells themselves. (Am J Pathol 2009, 174:957-909; DOI: 10.2353/ajpath.2009.080480)