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(Investigative Ophthalmology and Visual Science. 2008;49:2376-2383.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1067
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Induction of Amyloid β Accumulation by ER Calcium Disruption and Resultant Upregulation of Angiogenic Factors in ARPE19 Cells

Yoshihisa Koyama,1,2 Shinsuke Matsuzaki,1,2,3 Fumi Gomi,4 Kohei Yamada,1,2 Taiichi Katayama,5 Kohji Sato,5 Tatsuro Kumada,6 Atsuo Fukuda,6 Satoshi Matsuda,4 Yasuo Tano,4 and Masaya Tohyama1,2,3

1From the Departments of Anatomy and Neuroscience and 4Ophthalmology, and the 3Osaka-Hamamatsu Joint Research Center for Child Mental Development, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; the 221st Century COE Program; and the 5Departments of Anatomy and Neuroscience and 6Physiology, Hamamatsu University School of Medicine, Shizuoka, Japan.

PURPOSE. To investigate the intracellular mechanisms that induce amyloid β (Aβ) accumulation and angiogenesis in the human retinal pigment epithelial cell line ARPE19.

METHODS. The authors used two endoplasmic reticulum (ER) stress-inducing reagents, thapsigargin (TG), which inhibits the sarcoplasmic/endoplasmic calcium (Ca)2+-ATPase, and tunicamycin (TM), which inhibits N-linked glycosylation. The expression pattern of Aβ-precursor protein (APP) splice variants was investigated by reverse transcription (RT)-PCR. Cellular expressions of both a series of Aβ metabolism-related factors and angiogenic factors were evaluated by real-time RT-PCR and Western blot (VEGF). Expression of caspase-4 was examined by real-time RT-PCR and Western blot to evaluate the effect of the ER stressor. Intracellular Ca elevation by TG was evaluated by Ca2+ imaging experiments. Dimethyl sulfoxide and staurosporine were used as a nonreagent control and as an apoptosis-inducing reagent through mitochondria not ER, respectively.

RESULTS. TG-treated ARPE19 cells increased the mRNA expression of Aβ production-inducing APP splice variants and reduced that of neprilysin, a catabolic enzyme for Aβ. TG-treated ARPE19 cells produced increases in VEGF, TNF-{alpha}, TACE mRNA, and VEGF protein expressions and a decrease in PEDF mRNA expression. TG-treated ARPE19 cells induced the expression of active more than TM-treated casepase-4. The intracellular Ca concentration was elevated in only TG-treated ARPE19 cells.

CONCLUSIONS. TG-treated ARPE19 cells showed both Aβ accumulation-inducible and angiogenic factor mRNA expression patterns. This study suggests the possibility that ER stress through ER calcium disruption may induce the expression not only of Aβ deposit-promoting factors but also angiogenic factors in the retinal pigment epithelium.






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