Arsenic affects expression and processing of amyloid precursor protein (APP) in primary neuronal cells over expressing the Swedish mutation of human APP

Arsenic poisoning due to contaminated water and soil, mining waste, glass manufacture, select agrochemicals, as well as sea food, affects millions of people world wide. Recently, an involvement of arsenic in Alzheimer’s disease (AD) has been hypothesised (Gong and O’Bryant, 2010). The present study stresses the hypothesis whether sodium arsenite, and its main metabolite, dimethylarsinic acid (DMA), may affect expression and processing of the amyloid precursor protein (APP), using the cholinergic cell line SN56.B5.G4 and primary neuronal cells over expressing the Swedish mutation of APP, as experimental approaches. Exposure of cholinergic SN56.B5.G4 cells with either sodium arsenite or DMA decreased cell viability in a concentration – and exposure-time dependent manner, and affected the activities of the cholinergic enzymes acetylcholinesterase and choline acetyltransferase. Both sodium arsenite and DMA exposure of SN56.B5.G4 cells resulted in enhanced level of APP, and sAPP in the membrane and cytosolic fractions, respectively. To reveal any effect of arsenic on APP processing, the amounts of APP cleavage products, sAPPâ, and â-amyloid (Aâ) peptides, released into the culture medium of primary neuronal cells derived from transgenic Tg2576 mice, were assessed by ELISA. Following exposure of neuronal cells by sodium arsenite for 12 hours, the membrane-bound APP level was enhanced; the amount of sAPPâ released into the culture medium was slightly higher, while the levels of Aâ peptides in the culture medium were considerably lower as compared to that assayed in the absence of any drug. The sodium arsenite-induced reduction of Aâ formation suggests an inhibition of the APP ç-cleavage step by arsenite. In contrast, DMA exposure of neuronal cells considerably increased formation of Aâ and sAPPâ, accompanied by enhanced membrane APP level. The DMA-induced changes in APP processing may be the result of the enhanced APP expression. Alternatively, increased Aâ production may also be due to stimulation of caspase activity by arsenic compounds, or failure in Aâ degradation. In summary, the present report clearly demonstrates that sodium arsenite and DMA affect processing of APP in vitro.

Authors: Zarazua, Sergio; Buerger, Susanne; Delgado, Juan M.; Jimenez-Capdeville, Maria E.; Schliebs, Reinhard ;Full Source: International Journal of Developmental Neuroscience 2011, 29(4), 389-396 (Eng) ;