The E693Δ mutation in amyloid precursor protein increases intracellular accumulation of amyloid β oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells

Kazuchika Nishitsuji, Takami Tomiyama*, Kenichi Ishibashi, Kazuhiro Ito, Rie Teraoka, Mary P. Lambert, William L. Klein, Hiroshi Mori

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

The E693Δ mutation within the amyloid precursor protein (APP) has been suggested to cause dementia via the enhanced formation of synaptotoxic amyloid β (Aβ) oligomers. However, this mutation markedly decreases Aβ secretion, implying the existence of an additional mechanism of neuronal dysfunction that is independent of extracellular Aβ. We therefore examined the effects of this mutation on both APP processing to produce Aβ as well as subcellular localization and accumulation of Aβ in transfected HEK293 and COS-7 cells. Both β- and γ-cleavage of mutant APP increased, indicating a lack of inhibition in Aβ production. Instead, this mutation promoted Aβ 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 Aβ generation and/or degradation, suggesting impairment of APP/Aβ trafficking. Notably, the intracellular mutant Aβ was found to predominantly form oligomers. Concomitant with this accumulation, the ER stress markers Grp78 and phosphorylated eIF2α 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 Aβ induces alteration of Aβ trafficking and subsequent ER stress-induced apoptosis via enhancement of its intracellular oligomerization. Our findings suggest that Aβ oligomers exhibit toxicity in the extracellular space and within the cells themselves.

Original languageEnglish (US)
Pages (from-to)957-969
Number of pages13
JournalAmerican Journal of Pathology
Volume174
Issue number3
DOIs
StatePublished - Mar 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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