Arsenic Promotes Intracellular Aβ(1−42) Accumulation via Enhanced APP but Reduced NEP Expression, and Indirectly Stimulates Extracellular Aβ Aggregation through AChE Induction in Differentiated SH-SY5Y Cells
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Issued Date
2026-01-01
Resource Type
ISSN
01634984
eISSN
15590720
Scopus ID
2-s2.0-105033401542
Journal Title
Biological Trace Element Research
Rights Holder(s)
SCOPUS
Bibliographic Citation
Biological Trace Element Research (2026)
Suggested Citation
Leelaprachakul N., Visitnonthachai D., Niyomchan A., Maliphol K., Watcharasit P., Satayavivad J. Arsenic Promotes Intracellular Aβ(1−42) Accumulation via Enhanced APP but Reduced NEP Expression, and Indirectly Stimulates Extracellular Aβ Aggregation through AChE Induction in Differentiated SH-SY5Y Cells. Biological Trace Element Research (2026). doi:10.1007/s12011-026-05075-9 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/115925
Title
Arsenic Promotes Intracellular Aβ(1−42) Accumulation via Enhanced APP but Reduced NEP Expression, and Indirectly Stimulates Extracellular Aβ Aggregation through AChE Induction in Differentiated SH-SY5Y Cells
Corresponding Author(s)
Other Contributor(s)
Abstract
Arsenic exposure is associated with Alzheimer’s disease (AD) development through unclear mechanisms. This study investigated the effects of arsenic on amyloid-β (Aβ), a peptide linked to AD pathogenesis, in differentiated SH-SY5Y neuroblastoma cells. Arsenic increased intracellular Aβ<inf>(1−42)</inf> while decreasing its extracellular levels. It elevated amyloid precursor protein (APP) while decreasing a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a non-amyloidogenic secretase, suggesting a shift in APP processing toward an amyloidogenic pathway. Arsenic reduced intracellular neprilysin (NEP), an Aβ-degrading enzyme, while increasing its extracellular levels. Interestingly, Aβ<inf>(1−42)</inf> detection by immunogold transmission electron microscopy revealed that NEP restoration by humanin G (HNG) reduced arsenic-induced intracellular Aβ<inf>(1−42)</inf>. Thus, the inhibition of NEP moderately contributed to the arsenic-induced intracellular Aβ<inf>(1−42)</inf>. Thioflavin T (ThT) assay revealed that arsenic enhanced extracellular Aβ aggregation. Arsenic upregulated extracellular acetylcholinesterase (AChE), known to promote Aβ aggregation. Co-treatment with HNG, which reportedly prevented AChE-promoted Aβ aggregation, attenuated Aβ aggregation by arsenic. Accordingly, arsenic-elevated AChE possibly promotes extracellular Aβ aggregation. Overall, arsenic promotes intracellular Aβ<inf>(1−42)</inf> accumulation, possibly through the upregulation of APP and a decrease in the Aβ-degrading enzyme, NEP, and extracellular Aβ aggregation by AChE upregulation. As both Aβ intracellular accumulation and extracellular aggregation play pivotal roles in AD, our findings may provide insightful mechanistic links between arsenic and AD.