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

Abstract

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 hypothesized (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 overexpressing 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, sAPPβ, and β-amyloid (Aβ) 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 12h, the membrane-bound APP level was enhanced, the amount of sAPPβ released into the culture medium was slightly higher, while the levels of Aβ 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 Aβ formation suggests an inhibition of the APP γ-cleavage step by arsenite. In contrast, DMA exposure of neuronal cells considerably increased formation of Aβ and sAPPβ, accompanied by enhanced membrane APP level. The DMA-induced changes in APP processing may be the result of the enhanced APP expression. Alternatively, increased Aβ production may also be due to stimulation of caspase activity by arsenic compounds, or failure in Aβ degradation. In summary, the present report clearly demonstrates that sodium arsenite and DMA affect processing of APP in vitro.

The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review

“…For the purposes of this review, we will discuss arsenic exposure in the context of experimental studies. In vitro research using a cholinergic neuronal cell line has demonstrated that sodium arsenite and dimethylarsinic acid (DMA) have different effects on APP protein levels, β-amyloid formation, and altered activity of AchE and ChAT [94]. These findings corroborate our own: we have found altered mRNA expression of genes associated with AD, including Appb1 and ApoE , and Ache in the dentate gyrus of adult male mice after developmental exposure to 50 μg/L arsenic [72].…”

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

“…In a cell study conducted by Shavali and Sens (2007), arsenic was found to cause enhanced oxidative stress and cell death in cultured neuronal cells, when administered with dopamine [167]. In a study using a cholinergic neuronal cell line overexpressing amyloid precursor protein (APP) and exposing it to sodium arsenite and its metabolite, dimethylarsenic acid, it was found to affect cleavage of APP and increase its production [168]. …”

Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

“…ii) increased APP expression and B amyloid formation [34], iii) impaired synaptic transmission [35], increased tau protein phosphorylation [36,37], and reticulum endoplasmic stress induction [38].…”

“…Moreover, Zhao et al, 2011[23], demonstrated that pro-inflammatory cytokine combinations, like TNF-α plus IFN-γ , synergistically increase levels of endogenous APP and BACE1 in astrocytes, as compared to individual cytokines alone. On the other hand, As is reported to affect expression and processing of APP in neuronal cells [34,61]. Therefore, the connecting factor between arsenic-induced neurotoxicity and AβOs formation is very likely to be the As-induced inflammatory responses.…”