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Overexpression of C9orf72 exacerbates Aβ25-35-induced oxidative stress and apoptosis in PC12 cells

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is manifested by memory loss and spatial
disorientation. There is currently no effective treatment for AD. Abnormalities of the chromosome 9 open reading frame
72 (C9orf72) gene have been associated with various neurodegenerative diseases. However, its intrinsic roles in AD remain
to be elucidated. Here we found that Aβ25‑35 increased the expression of C9orf72 in PC12 cells at both mRNA and protein
levels. In Aβ25‑35‑treated PC12 cells, C9orf72 overexpression induced an abnormally condensed and fragmented nucleus and
apoptosis, as well as significantly enhanced reactive oxygen species (ROS) levels. Mechanistically, an Aβ25‑35‑induced decrease
of superoxide dismutase activity was augmented by C9orf72 overexpression, which in contrast increased malondialdehyde
content. Consistently, further apoptotic analysis revealed significant downregulation of Bcl‑2 and Bcl‑xL expression and
enhanced cleavage of caspase‑3 with Aβ25‑35 treatment, all of which were exacerbated by C9orf72 overexpression. In addition,
tau phosphorylation, another hallmark of AD pathology, was induced by Aβ25‑35 and was remarkably enhanced by C9orf72
overexpression. Our data indicate that C9orf72 plays important roles in intracellular ROS signaling and Aβ25‑35‑induced neuronal
apoptosis in AD. These findings provide insights into C9orf72 function in the pathogenesis of many related neurodegenerative
diseases and provide a basis for potential therapeutic interventions.