The association between prion proteins and Aβ1–42 oligomers in cytotoxicity and apoptosis

Misfolding of prion protein (PrP to PrPSc) can cause neurodegenerative prion diseases. As a glycosylphosphatidylinositol (GPI)-anchored membrane protein, the normal form of PrP (PrPC) can function as a receptor for ligands in the extracellular space. PrPC was suggested to be involved in memory, synaptic neuronal communication, and anti-oxidation as a neuroprotective agent. The recently identified interaction between PrPC and Aβ1–42 oligomers suggested another role for PrP as a receptor for Aβ1–42 oligomers, thereby influencing cytotoxicity and apoptosis.Here, the association between PrPC and Aβ1–42 oligomers was investigated by visualizing protein localization in neuronal cells by immunocytochemistry. Aβ1–42 oligomer-induced cytotoxicity was tested in respective expressions of PrPC by using mouse neuroblastoma-2a (N2a) cells, the prion protein overexpressed cells (L2-2B1), and a Prnp-null mouse hippocampal cell line (HpL 3–4). Moreover, apoptotic proteins such as caspase-8 were used to assess the effect of PrPC on Aβ1–42 oligomer-mediated apoptosis. In L2-2B1 and HpL 3–4 cells, the difference in the cytotoxicity of Aβ1–42 oligomers could be clearly distinguished. In addition, Aβ1–42 oligomers induced mitochondria dysfunction, reactive oxygen species (ROS) generation, and calcium influx PrPC-dependently. Apoptosis, related to mitochondria dysfunction, was further investigated to determine the cytotoxic pathway; the results suggest that PrPC could be involved in both the intrinsic and extrinsic apoptotic pathways. Finally, cells with abundant PrPC expression seemed to be more susceptible to Aβ1–42 oligomer toxicity, suggesting the importance of the level of PrPC expression in the induction of apoptosis.

► PrPC overexpressed cells were more susceptible to cytotoxicity induced by Aβ1–42 oligomer.
► PrPC deficient cells had less influenced to cytotoxicity than N2a cells, which has normal PrPC level.
► Aβ1–42 oligomers could facilitate apoptosis, when PrPC was abundant.
► PrPC may not be limited to prion diseases, but a protector or killer in disease pathogenesis.